聚焦哺乳动物眼晶状体：发育、解剖、生理、透明性、生物力学及与年龄相关的问题

Catherine Cheng; Michael P. Vu

doi:10.3791/70442

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综述文章

聚焦哺乳动物眼晶状体：发育、解剖、生理、透明性、生物力学及与年龄相关的问题

162 次观看

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DOI：

10.3791/70442

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2026年5月29日

Catherine Cheng¹ , Michael P. Vu¹

¹School of Optometry and Vision Science Program, Indiana University

本文内容

摘要

晶状体通过将光线聚焦到视网膜上以实现其功能，该功能依赖于组织的透明度、生物力学特性以及折射率。本文综述了晶状体的三维结构，并探讨了维持组织稳态的复杂机制。

摘要

晶状体是位于眼球前房内的透明椭球状器官，可将光线聚焦到视网膜上。该三维组织由上皮细胞和纤维细胞构成，结构高度有序，以确保光路清晰，并通过多种机制建立和维持高折射率与透明性。在人类中，晶状体通过改变形状来聚焦不同距离的光线，这一过程称为调节；晶状体的弹性与生物力学特性依赖于组织、细胞和分子层面的机制。白内障是指原本透明的晶状体出现任何混浊，仍是全球致盲的首要原因。老花眼则与年龄相关的晶状体硬化有关，已被证实与调节能力下降及需要佩戴阅读眼镜相关。本文综述将探讨哺乳动物晶状体的发育与终身生长、晶状蛋白与细胞骨架蛋白、细胞间通讯与微循环、晶状体生物力学，以及研究这一独特组织所面临的挑战与新兴方法。

引言

晶状体乍看之下是一种相对简单的组织，由两种细胞类型构成：上皮细胞和纤维细胞。晶状体的大部分质量由纤维细胞组成，其前半球表面覆盖着一层单层的上皮细胞¹（图1A）。整个组织被一层称为晶状体囊膜的薄基底膜包裹，该膜主要由IV型胶原蛋白和层粘连蛋白构成，如先前综述所述²。晶状体无血管和神经供应，通过连接晶状体囊膜与睫状体的弹性悬韧带纤维（又称悬韧带）悬挂在眼球前房内¹。位于晶状体前部或中央的上皮细胞呈立方形，排列成鹅卵石样结构³^,⁴^,⁵（图1A，浅蓝色细胞，顶部）。这些细胞处于静止状态，不发生增殖⁶。在晶状体赤道区前方，上皮细胞在生发区分裂（图1A，橙色细胞，右上），这些赤道区细胞将向赤道迁移，并排列成高度有序的子午线状行列，细胞呈六边形⁷^,⁸^,⁹^,¹⁰（图1A，绿色细胞，右上）。子午线行列细胞将其顶端锚定于晶状体的支点（即中轴部），随后开始伸长并分化为新的次级纤维细胞（图1A，左下）。次级纤维细胞的顶端通过与上皮细胞顶端面相互作用，向晶状体前极迁移，形成一种特殊的顶端-顶端连接结构³（图1A，红线）。新形成的纤维细胞的后端基底端沿晶状体囊膜向后极延伸（图1A，左下）。当伸长中的纤维细胞末端到达前极或后极时，细胞从前部上皮细胞或后部囊膜脱离，并与来自组织对侧延伸而来的细胞末端相遇，形成缝合线结构¹¹^,¹²^,¹³（图1A，左上）。晶状体纤维细胞横截面呈拉长的六边形，具有两个长/宽边、四个短边以及六个三细胞连接结构（图1A，右下）¹⁴。相邻纤维细胞之间极小的细胞间隙有助于减少光散射¹⁴。皮质区纤维细胞在周边持续添加，并叠加于先前生成的纤维层之上，从而支持晶状体终生生长¹⁴^,¹⁵。晶状体中心区域称为晶状体核，该区域的硬度高于周边部或皮质区，如先前综述所述¹⁶。

晶状体解剖结构示意图，显示结构层次、上皮细胞、纤维的扫描电镜图像以及光线通过路径。
图1：晶状体的解剖结构与组织构成。 (A) 晶状体由覆盖前半球的一层上皮细胞（浅蓝色、橙色和浅绿色）以及大量晶状体纤维（白色和粉色）构成。一层薄的胶原膜，称为晶状体囊膜（棕褐色），包裹着整个组织。晶状体通过悬韧带纤维（悬韧带）插入晶状体赤道部周围的囊膜，从而悬浮于眼球前房中。位于前部/中央区域的上皮细胞（顶部浅蓝色）呈立方形，横切面呈鹅卵石状。生发区的赤道部上皮细胞（橙色）从随机排列的细胞（橙色）转变为有序的六边形细胞的经向排列（绿色）。这些经向排列的细胞伸长，成为晶状体周边部的新皮质次级纤维细胞层（白色）。新生次级纤维的顶端锚定在支点/中央柱（左下部海螺色方框）。伸长中的次级纤维顶端沿晶状体上皮细胞的顶端侧面向前极迁移，并形成一种特殊的顶端-顶端连接（红线）。伸长中纤维的基底端则沿后囊膜向后极迁移。当次级纤维完全伸长后，其末端从前部上皮或后囊膜脱离，形成晶状体缝合线（深蓝色线条及左上图像）。晶状体纤维细胞横切面呈拉长的六边形（右下），具有2个长/宽边、4个短边以及6个三细胞连接。在纤维细胞成熟过程中，所有细胞器均被清除，形成无细胞器区（深绿色双向箭头），以最大限度减少光散射。最古老的晶状体纤维细胞被压缩至组织中心，形成晶状体核（粉色）。示意图未按实际比例绘制。(B) 扫描电子显微镜图像显示了晶状体不同深度处纤维细胞的形态变化，反映了细胞分化与成熟过程中的形态演变。为突出显示，单个细胞以绿色标出。皮质外周纤维的长边具有球窝状嵌合结构，短边则带有小突起。在纤维细胞成熟过程中，成熟细胞的短边出现由小突起装饰的大桨状结构以及大型突起。核周纤维在整个膜上具有舌槽状嵌合结构，短边带有大型突起。核区纤维的短边具有大型突起，并呈现球状膜形态。比例尺：5 µm。改编自¹⁶^,³²⁸。请点击此处查看该图的放大版本。

晶状体的复杂性在于其高度有序的三维（3D）细胞排列、特化的纤维细胞成熟过程（该过程会降解并清除所有细胞器），以及建立和维持组织透明性和高折射率的分子与细胞机制。大多数晶状体纤维细胞中细胞器的缺失，增加了在整个生物体生命周期中维持每个晶状体细胞健康与长寿的难度。晶状体是研究衰老及与年龄相关变化的理想组织，因为其中心最深处的细胞是在胚胎早期发育阶段形成的，而晶状体在整个生命过程中持续于组织周边区域生成新细胞，从而允许对时间上较老的细胞与在老年时期生成的细胞进行比较研究。晶状体的精细聚焦功能使来自不同距离物体的清晰图像能够投射到视网膜上，这一功能依赖于晶状体改变自身形状或进行调节的能力。晶状体是一种非结缔组织、非肌肉组织，其正常功能依赖于特定的生物力学特性。

导致视力障碍的首要原因是衰老¹⁷。与年龄相关的变化会引起两种主要的晶状体病变：白内障和老视¹⁸。白内障或任何晶状体混浊仍是全球致盲的首要原因¹⁹，其成因包括遗传和环境因素，如紫外线辐射、吸烟、糖尿病和氧化应激，这些因素会导致蛋白质聚集和/或细胞缺陷，如先前综述所述¹⁸^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵。老视是一种与年龄相关的调节能力下降，由晶状体在聚焦近处物体时改变形状的能力减弱所致，进而导致需要佩戴阅读眼镜²⁶^,²⁷^,²⁸。世界卫生组织估计，全球至少有10亿人存在未被矫正的视力障碍，其中包括6520万白内障患者和8.26亿老视患者¹⁷。随着人口老龄化加剧，迫切需要更深入地理解晶状体的生理学与生物学特性。

本文综述了对哺乳动物晶状体功能和稳态至关重要的组织结构、细胞排列方式及分子机制，并简要介绍了其他脊椎动物晶状体的相关信息。本文旨在提供晶状体生物学与生理学的总体概述，并附有更多详细综述的参考文献。内容涵盖胚胎期晶状体发育、出生后晶状体生长、细胞与组织的三维排列结构、组织的生物力学特性以及微循环系统。下文将讨论晶状体中的主要蛋白质，即晶状蛋白、细胞骨架网络以及细胞间通讯。最后，本文将总结当前研究这一独特组织所面临的主要挑战以及新兴的研究方法。

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综述与观点

胚胎晶状体发育与出生后晶状体生长

在脊椎动物中，晶状体由表面外胚层细胞发育而来，未来的晶状体始于视泡上方表面外胚层的增厚⁶^,²⁹^,³⁰（图2A）。随着视杯的形成，增厚的外胚层（即晶状体板）向内凹陷形成晶状体凹陷⁶^,²⁹^,³⁰（图2B）。肌动蛋白丝（F-actin）将晶状体凹陷的后部与发育中的视杯前表面连接，以协调这些发育中组织的运动和形态变化³¹^,³²^,³³^,³⁴，而晶状体上皮细胞的顶端收缩是晶状体凹陷内陷所必需的³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰（图2C）。晶状体凹陷的开口持续变窄，直至闭合，此过程中晶状体茎细胞发生凋亡⁴¹^,⁴²^,⁴³。晶状体泡与未来角膜外胚层分离，形成由单层上皮细胞构成的中空球形结构——晶状体泡⁶^,²⁹^,³⁰（图2D）。晶状体泡中的后部上皮细胞向前沿着前部上皮方向伸长，并分化为初级纤维细胞，填充腔隙，形成胚胎期晶状体（图2E）。覆盖前半球的单层上皮细胞得以维持，而在完全形成的胚胎晶状体中已无后部上皮细胞（图2F）。初级纤维细胞构成晶状体核最中心的部分，其外周则被终生从晶状体周边部或皮质不断添加的新一代次级晶状体纤维所包围⁶^,²⁹^,³⁰。尽管大多数脊椎动物的晶状体通过内陷方式形成，但在斑马鱼中，晶状体板增厚后通过去层化的方式形成晶状体⁴⁴。

眼睛发育阶段：晶状体板、凹陷、泡状结构及胚胎晶状体形成过程示意图。
图 2：哺乳动物眼睛的胚胎晶状体发育过程。 表面外胚层细胞为白色，晶状体细胞为浅蓝色，视杯/视泡细胞为沙色。（A） 胚胎晶状体板（浅蓝色）由表面外胚层发育而来。位于表面外胚层和晶状体板后方的是视泡。（B） 晶状体板内陷形成晶状体凹，视泡内陷形成视杯。视杯的前部将发育为虹膜和睫状体，而后部将形成视网膜和视网膜色素上皮。（C） 晶状体板开口逐渐变窄，直至完全闭合。（D） 晶状体泡从表面外胚层分离，形成一个由晶状体上皮细胞衬里的中空球体。（E） 晶状体泡内后部的晶状体上皮细胞开始伸长并分化为初级晶状体纤维。（F） 初级晶状体纤维填充晶状体泡腔，形成胚胎晶状体。示意图未按比例绘制。仿照 ⁴¹¹ 修改。请点击此处查看该图的放大版本。

在胚胎发育过程中，晶状体被一种篮状的血管网络所包围⁶^,⁴⁵^,⁴⁶。这些血管起源于视网膜的玻璃体动脉，最初在晶状体凹陷的后方开始形成网络，最终构建出有序的晶状体血管膜（tunica vasculosa lentis），以滋养胚胎期的晶状体，直至前房结构和房水生成完全发育成熟⁶^,⁴⁵。这些血管随后退化并消失，以确保在出生前或睁眼前（取决于物种）形成清晰的光路⁶^,⁴⁵^,⁴⁶^,⁴⁷。

Pax6 对早期眼睛发育是必需的⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²，并且对晶状体发育至关重要且足以驱动其发育⁵³^,⁵⁴^,⁵⁵^,⁵⁶。Pax6 的磷酸化和 SUMO 化修饰可调控该转录因子在脑、中枢神经系统及眼睛发育过程中的功能⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰。其他对胚胎眼睛和晶状体发育至关重要的信号通路与 Pax6 信号通路相互交汇，包括增强子因子 [Meis、骨形态发生蛋白（Bmp）和成纤维细胞生长因子（FGF）] 以及下游蛋白 [Foxe3 和视黄酸（RA）]，如先前综述所述⁶¹。Meis1 和 Meis2 可结合至 Pax6 基因的增强子区域，在脊椎动物晶状体诱导过程中发挥必需作用⁶²。遗传学研究表明，Bmp7 通过调控 Pax6 的表达，对晶状体基板的发育至关重要⁶³^,⁶⁴。Foxe3 位于 Pax6 信号通路的下游，对晶状体发育必不可少⁶⁵^,⁶⁶，尤其是在晶状体泡形成时，介导晶状体柄与表面外胚层的清晰分离。Foxe3 缺失会导致一种称为彼得异常（Peters Anomaly）的先天性眼部缺陷⁶⁷。成纤维细胞生长因子受体（FGFR）信号通路与 Bmp7 协同作用，调控 Pax6 的表达，进而影响发育中晶状体内的 Foxe3 水平⁶⁸。表达一种抑制性 FGFR 形式会导致晶状体基板形成延迟、晶状体柄分离不完全以及晶状体泡体积变小⁶⁸。视黄酸（RA）信号通路的破坏会导致眼部形成缺陷⁶⁹，而当 Pax6 受到干扰时，RA 的表达水平降低，提示这两条信号通路之间存在一定的交互作用⁷⁰。

胚胎晶状体完全形成后，晶状体的持续生长被认为主要通过赤道部上皮细胞增殖并分化为次级晶状体纤维来实现，这一过程主要由生长因子信号通路驱动，其中哺乳动物晶状体中以成纤维细胞生长因子（FGF）信号通路为主，如先前综述所述⁷¹。FGF在玻璃体中的含量高于房水，从而在晶状体赤道区附近形成生长和分化信号的浓度梯度⁷²^,⁷³。晶状体表达4种FGF受体（FGFR）中的3种，即FGFR1、FGFR2和FGFR3，其表达水平在晶状体赤道区及赤道后区域逐渐升高⁷⁴^,⁷⁵。FGF的过表达可诱导原本静息的前部上皮细胞异常伸长并分化为类纤维细胞⁷⁶^,⁷⁷^,⁷⁸。除FGF信号通路外，抑制剂实验表明Bmp通路在纤维细胞伸长过程中也发挥作用⁷⁹^,⁸⁰，而异常的转化生长因子β（TGFβ）受体则会破坏纤维细胞的正常成熟过程⁸¹。

晶状体透明度与折射率

晶状体纤维细胞在成熟过程中会经历一种特化的程序，以清除所有细胞器，从而消除光线传播路径中的散射物，并形成无细胞器区（OFZ）⁸² （图1A）。当纤维细胞达到其成熟程序的特定阶段后，所有细胞器的协调性丢失会迅速发生⁸³^,⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸。细胞器降解异常可导致白内障，已有多个基因敲除（KO）斑马鱼和小鼠模型鉴定了与染色质和DNA降解⁸⁹^,⁹⁰^,⁹¹^,⁹²^,⁹³、周期蛋白依赖性激酶⁹⁴^,⁹⁵、热休克因子4⁹¹^,⁹⁶^,⁹⁷^,⁹⁸以及PLATT磷脂酶⁹⁹相关的基因，这些基因对OFZ的形成至关重要。细胞膜和细胞骨架蛋白¹⁰⁰^,¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁴、晶状体蛋白（crystallins）¹⁰⁵^,¹⁰⁶^,¹⁰⁷以及癌基因¹⁰⁸^,¹⁰⁹的异常表达或突变也会影响细胞器的清除及晶状体透明度。然而，触发纤维细胞中细胞器降解的确切信号仍不明确。近期研究揭示了RNA结合蛋白在晶状体发育和白内障发生中的重要作用，如先前综述所述¹¹⁰。RNA结合蛋白的功能障碍，包括Tdrd7¹¹¹、caprin2¹¹²、Rbm24¹¹³和Celf1¹¹⁴^,¹¹⁵^,¹¹⁶，可导致晶状体发育异常、细胞器降解受阻以及白内障的形成。

与体内大多数细胞类型相比，哺乳动物晶状体纤维细胞的蛋白质浓度极高（200–450 mg/ml）¹¹⁷^,¹¹⁸^,¹¹⁹^,¹²⁰。蛋白质占晶状体总重量的30%–35%，因此晶状体含水量相对较低，约为65%–70%¹²¹^,¹²²。按质量计，晶状体蛋白质中有90%为晶状蛋白¹²³，哺乳动物晶状体中存在三类晶状蛋白家族：α、β和γ，如先前综述所述¹²⁴^,¹²⁵。通常情况下，高蛋白浓度会增加大于光波长一半的聚集体形成风险，从而导致光散射¹²⁶，但晶状蛋白在纤维细胞胞质中以短程有序的方式排列，有助于提高折射率并维持透明性¹¹⁷^,¹²⁷。α-晶状蛋白具有类似分子伴侣的功能，可抑制蛋白质聚集，下文将对此进行讨论。晶状体内部的梯度折射率（GRIN）有助于光线聚焦，如先前综述所述¹²⁸^,¹²⁹，晶状体中心的最大折射率与核部纤维细胞的致密化相关¹³⁰^,¹³¹^,¹³²。在鱼类晶状体中，数据表明核部高折射率是蛋白质向组织中心转运的结果¹³³。人们推测，晶状蛋白在细胞内及纤维层之间的均匀分布可能通过沿纤维细胞膜形成的膜融合介导的大分子转运途径实现¹³⁴^,¹³⁵。然而，在小鼠晶状体中尚未明确观察到膜融合结构¹³⁶^,¹³⁷^,¹³⁸，且对多种物种晶状体进行的阻抗研究也未检测到膜融合的存在¹³⁹^,¹⁴⁰^,¹⁴¹^,¹⁴²。来自间隙连接通讯受损的小鼠模型的数据表明，细胞间通讯和纤维细胞的伸长也有助于大分子转运途径的实现¹⁴³。

晶状体蛋白的分子量约为 20–30 kDa，在晶状体中发挥结构和折射作用。α-晶状体蛋白由 αA 和 αB 两个亚基组成，二者具有 55%–60% 的同源性¹⁴⁴^,¹⁴⁵^,¹⁴⁶。尽管 αB 在大多数细胞中广泛表达，αA-晶状体蛋白则主要在晶状体中表达，并在脾脏和胸腺等其他组织中以低水平被检测到¹⁴⁷^,¹⁴⁸。最近的研究还表明，视网膜色素上皮细胞和视网膜神经节细胞在应激或疾病状态下可表达 αA-晶状体蛋白，可能起到神经保护作用¹⁴⁹^,¹⁵⁰^,¹⁵¹。α-晶状体蛋白通常形成由 30–35 个混合的 αA 和 αB 亚基组成的大型异源多聚体¹²³。在小鼠、牛和人晶状体上皮中，前部细胞仅检测到 αB，赤道部细胞中 αA 与 αB 的比例为 1:3；在次级纤维细胞分化和伸长过程中，该比例转变为 3:1¹²³^,¹⁵²^,¹⁵³。α-晶状体蛋白属于小热休克蛋白家族，具有类似分子伴侣的功能¹⁵⁴，能够结合并隔离异常或未折叠的蛋白质，防止进一步的蛋白质聚集。已有研究探索使用小片段 α-晶状体蛋白肽来预防由蛋白质聚集引起的疾病（包括白内障），如先前综述所述¹⁵⁵。然而，在小鼠模型中，α-晶状体蛋白的类伴侣活性增强或减弱均会导致白内障严重程度增加，表明适当的类伴侣活性对维持晶状体透明至关重要¹⁵⁶。β-和 γ-晶状体蛋白属于独立的 β/γ-晶状体蛋白家族，具有纤维细胞特异性；在哺乳动物中，β-晶状体蛋白有 7 种亚型，以二聚体、四聚体或更高阶的寡聚体形式存在，而 γ-晶状体蛋白也有 7 种亚型，均为单体，如先前综述所述¹²⁵。除了结构功能外，β-和 γ-晶状体蛋白还能结合钙离子，调节晶状体纤维中的钙离子可用性和储备¹⁵⁷^,¹⁵⁸^,¹⁵⁹^,¹⁶⁰^,¹⁶¹。

晶状体细胞骨架与膜蛋白

晶状体上皮细胞和纤维细胞中含有F-肌动蛋白、角蛋白或波形蛋白中间丝、特化的串珠状中间丝以及微管网络，这些结构已在先前的综述中有所描述¹⁶²^,¹⁶³^,¹⁶⁴^,¹⁶⁵^,¹⁶⁶。除了在眼和晶状体发育过程中发挥功能³¹^,³²^,³³^,³⁴外，晶状体上皮细胞和纤维细胞中多种多样的F-肌动蛋白网络对维持晶状体透明性也至关重要¹⁶⁷^,¹⁶⁸^,¹⁶⁹^,¹⁷⁰^,¹⁷¹^,¹⁷²。近期研究表明，F-肌动蛋白网络的改变会影响晶状体的生物力学特性¹⁷³^,¹⁷⁴^,¹⁷⁵^,¹⁷⁶。由波形蛋白或角蛋白组成的中间丝分别仅存在于晶状体纤维细胞分化的早期阶段或胚胎发育期间¹⁷⁷^,¹⁷⁸^,¹⁷⁹^,¹⁸⁰^,¹⁸¹；相比之下，所有晶状体纤维均含有由filensin（又称CP95/CP115，由Bsfp1编码）和CP49（又称phakinin，由Bsfp2编码）形成的异源二聚体构成的串珠状中间丝¹⁸²^,¹⁸³^,¹⁸⁴。这些异源二聚体呈现串珠状结构，是由于CP49和filensin形成的寡聚体装饰在纤维核心上¹⁸⁵^,¹⁸⁶，以及α-晶状体蛋白结合于这些特化的中间丝上所致¹⁸⁷^,¹⁸⁸^,¹⁸⁹^,¹⁹⁰^,¹⁹¹。任一filensin或CP49的缺失均会导致该网络完全丧失¹⁹²^,¹⁹³^,¹⁹⁴^,¹⁹⁵。波形蛋白中间丝或串珠状中间丝的破坏可在人类及动物模型中引发白内障¹⁹²^,¹⁹³^,¹⁹⁶^,¹⁹⁷^,¹⁹⁸^,¹⁹⁹^,²⁰⁰^,²⁰¹^,²⁰²^,²⁰³^,²⁰⁴，表明这些细胞骨架网络对晶状体透明性具有重要意义。最近的研究提示，微管在晶状体纤维细胞的伸长²⁰⁵^,²⁰⁶以及无细胞器区的形成中发挥重要作用¹⁷⁷。

与肌动蛋白细胞骨架相互作用的黏附连接对于晶状体形成²⁰⁷和纤维细胞分化至关重要。E-钙黏蛋白和N-钙黏蛋白均在晶状体上皮细胞中表达²⁰⁸^,²⁰⁹^,²¹⁰^,²¹¹，且在纤维细胞分化开始时E-钙黏蛋白表达被关闭²¹²。N-钙黏蛋白在晶状体纤维细胞中高表达，并富集于伸长中纤维细胞基底六角形足部的中点处⁸^,²⁰⁹。在初级纤维细胞形成后若缺失N-钙黏蛋白，会导致次级纤维细胞伸长受阻，原因是分化中纤维细胞的顶端尖端沿前部上皮细胞顶面异常迁移²¹³。晶状体中Eph-ephrin双向信号传导的中断会引起黏附连接的缺陷⁴^,⁷^,²¹⁴^,²¹⁵^,²¹⁶。

其他主要的晶状体膜蛋白包括水通道蛋白（aquaporins）；连接蛋白（connexins）；MP20（如先前综述所述²¹⁷）；半乳糖凝集素3（galectin 3）；半乳糖凝集素相关纤维间蛋白（galectin-related interfiber protein, GRIFIN）；整合素（integrins）（如先前综述所述²¹⁸）；以及富含半胱氨酸的酸性分泌蛋白（secreted protein acidic and rich in cysteine, SPARC）。水通道蛋白和连接蛋白将在下一节中讨论。MP20（又称MP17或Lim2）是一种晶状体特异性的膜蛋白，具有细胞间黏附功能⁸⁵^,²¹⁹，在晶状体纤维细胞中含量丰富²²⁰^,²²¹；MP20的突变可导致白内障²²²^,²²³^,²²⁴^,²²⁵^,²²⁶^,²²⁷^,²²⁸^,²²⁹^,²³⁰。最近的研究表明，MP20与另一种重要的细胞间黏附分子——半乳糖凝集素3之间存在相互作用²³¹^,²³²^,²³³。GRIFIN是半乳糖凝集素的一种晶状体特异性异构体，定位于纤维细胞膜，并与Pax6、晶状体蛋白（crystallins）和钙黏蛋白（cadherins）相互作用²³⁴^,²³⁵^,²³⁶^,²³⁷。整合素是连接细胞外基质（extracellular matrix, ECM）与细胞骨架的重要连接分子，对晶状体的正常发育至关重要。在晶状体中表达的整合素异构体可作为囊膜成分（如层粘连蛋白、胶原蛋白或纤连蛋白）的受体⁸^,²³⁸^,²³⁹^,²⁴⁰^,²⁴¹^,²⁴²^,²⁴³^,²⁴⁴^,²⁴⁵。每种基质成分均可与多种整合素相互作用，通过整合素在晶状体发育和生长过程中的时空表达，引发多样化的信号传导²¹⁸。目前特别关注白内障手术后残余晶状体上皮细胞发生上皮-间质转化过程中TGFβ、整合素及ECM组分的变化，这些变化可导致后囊混浊，相关机制已在先前的综述中描述²¹⁸。SPARC是一种参与细胞间黏附和增殖的分子，定位于晶状体上皮细胞，而在分化中的纤维细胞中缺失²⁴⁶。SPARC的缺失可导致白内障²⁴⁶^,²⁴⁷^,²⁴⁸，最近的研究还表明，SPARC可能具有类似分子伴侣的功能²⁴⁹，可影响整合素和ECM蛋白²⁵⁰^,²⁵¹^,²⁵²，并调控微循环通路²⁵³。

无血管组织的微循环通路

由于缺乏血液供应，完全形成的晶状体可自主生成微循环通路以输送营养物质并清除代谢废物，如先前综述所述²⁵⁴^,²⁵⁵^,²⁵⁶^,²⁵⁷。离子电流从晶状体的前极和后极进入，并在赤道区流出²⁵⁸。内向电流依赖于钠离子沿浓度梯度从两极的晶状体细胞间细胞外间隙流入，该浓度梯度由主动运输建立；而外向电流则通过集中在晶状体赤道区附近的纤维细胞膜上的缝隙连接通道介导，使钠离子可在赤道区流出²⁵⁹。赤道部上皮细胞和周边纤维细胞高表达Na⁺/K⁺ ATP酶泵，主动将3个钠离子泵出细胞，同时将2个钾离子从晶状体外环境泵入细胞内²⁶⁰^,²⁶¹^,²⁶²。晶状体维持高钾浓度（135 mM）和低钠浓度（16 mM），从而建立钠离子在两极沿浓度梯度重新进入晶状体的条件²⁵⁹^,²⁶³。除了Na⁺/K⁺ ATP酶外，离子共转运体Na-K-2Cl共转运体1（NKCC1）也通过机械敏感通道的激活参与调节晶状体内的离子浓度，如先前综述所述²⁶⁴。

晶状体中的间隙连接由三种连接蛋白（connexin）组成，分别为连接蛋白43（Cx43或α1）、Cx46（或α3）和Cx50（或α8）²⁶⁵^,²⁶⁶。Cx43主要在晶状体上皮细胞中表达²⁶⁷；尽管在Cx43基因敲除（KO）晶状体中纤维细胞的形成起始正常，但上皮细胞与纤维细胞之间的界面出现扩大的细胞外间隙和细胞内空泡，提示Cx43在渗透平衡中具有功能作用²⁶⁸。Cx46主要集中于晶状体纤维细胞，而Cx50则存在于上皮细胞和纤维细胞中²⁶⁹。Cx23也在小鼠晶状体的纤维细胞中表达，但在人晶状体中不表达²⁷⁰^,²⁷¹^,²⁷²^,²⁷³。Cx23的显性突变会导致小鼠纤维细胞缺陷²⁷⁰，但Cx23基因敲除晶状体未表现出明显缺陷²⁷⁴。六个连接蛋白亚单位组成一个连接子（connexon）或半通道（hemichannel），一个细胞上的连接子与相邻细胞上的连接子对接形成间隙连接，从而在相邻细胞之间形成约10埃的孔道，允许小分子、离子和水的交换²⁷⁵^,²⁷⁶。连接蛋白半通道允许物质在细胞质与细胞外环境之间通过，如先前综述所述²⁷⁷^,²⁷⁸，半通道在微循环²⁷⁹、机械敏感性营养物质和抗氧化剂的转运²⁸⁰^,²⁸¹^,²⁸²^,²⁸³以及氧化应激反应中具有重要作用²⁸⁴^,²⁸⁵^,²⁸⁶^,²⁸⁷^,²⁸⁸。间隙连接在纤维细胞膜上聚集形成大的斑块；在晶状体中，这些斑块直径可达微米级，并沿相邻纤维细胞的长边排列²⁸⁹。小鼠晶状体中Cx46的缺失会因阻断晶状体微循环的流出通路而导致致密的核性白内障²⁹⁰^,²⁹¹。纤维细胞膜上大型Cx46斑块的组装和/或稳定性依赖于F-actin和串珠状中间丝网络²⁸⁹。Cx50基因敲除会导致小眼球、轻度核性白内障以及因上皮细胞增殖异常而导致的小晶状体²⁹²^,²⁹³。Cx50的缺失会影响晶状体纤维细胞中剩余Cx46间隙连接斑块的门控功能¹³⁹。在内源性Cx50位点通过基因敲入表达Cx46（4个拷贝的Cx46）可替代Cx50，从而挽救因Cx50缺失引起的白内障，并增强纤维细胞间的间隙连接偶联，但这些透明的敲入晶状体仍保持较小体积¹⁴²^,²⁹⁴。因此，Cx46无法替代Cx50在晶状体生长中的功能。该基因敲入策略也被用于挽救由γB-晶状体蛋白突变蛋白引起的核性白内障，表明增强间隙连接偶联可能是改善晶状体稳态和预防白内障的一种策略²⁹⁵。

钠离子产生的离子流伴随水通过水通道蛋白通道流入晶状体细胞²⁵⁹。水通道蛋白在上皮细胞中由Aqp1组成，而在晶状体纤维细胞中则由Aqp0（又称MIP）和Aqp5构成水通道，其组成取决于细胞的成熟程度，如先前综述所述²⁶⁴^,²⁹⁶^,²⁹⁷。水通过缝隙连接通道的移动在晶状体内形成静水压梯度²⁹⁸^,²⁹⁹，该梯度通过瞬时受体电位香草素1（TRPV1）和TRPV4机械敏感性通道维持晶状体的渗透压，分别增加和降低晶状体静水压²⁹⁹^,³⁰⁰^,³⁰¹^,³⁰²。晶状体上悬韧带张力降低会减少静水压，从而激活TRPV1，继而激活NKCC1，增加晶状体内离子浓度，驱动水流入晶状体以恢复正常的静水压³⁰⁰^,³⁰¹。相反，悬韧带张力和晶状体体积增加会激活TRPV4，继而激活Na⁺/K⁺ ATP酶，降低晶状体内离子浓度，从而降低静水压³⁰⁰^,³⁰¹^,³⁰²。

必需营养物质和氨基酸通过微循环途径被运输到晶状体中³⁰³，这种运输对OFZ纤维尤为重要。晶状体上皮细胞和纤维细胞中存在易化型葡萄糖转运蛋白（GLUT）；GLUT1在两种细胞类型中均有表达，而GLUT3仅在上皮细胞中表达³⁰⁴^,³⁰⁵^,³⁰⁶^,³⁰⁷。GLUT1基因敲除小鼠会发展为白内障，表明葡萄糖摄取对维持晶状体透明性至关重要³⁰⁸。谷胱甘肽（GSH）是维持晶状体透明性的重要抗氧化剂³⁰⁹^,³¹⁰，其在晶状体内合成，并可从房水中转运进入晶状体³¹¹^,³¹²^,³¹³^,³¹⁴^,³¹⁵。半胱氨酸、谷氨酸和甘氨酸是合成GSH所需的必需氨基酸，这些氨基酸在晶状体的皮质区和核区均有积累³¹⁴^,³¹⁵。随着年龄增长，GSH的合成减少或消耗增加，可导致晶状体中特别是核区GSH的可用性下降³¹⁶^,³¹⁷^,³¹⁸^,³¹⁹^,³²⁰^,³²¹。谷胱甘肽过氧化物酶（GPX）以GSH作为辅酶来中和氢过氧化物，近期研究表明，由于毒性脂质过氧化物引起的铁死亡可因GPX4功能受损而导致白内障³²²^,³²³。

三维晶状体结构与生物力学

晶状体纤维排列成有序的六边形细胞行，其起源在于赤道部上皮细胞排列成子午线行（图1A）。驱动随机排列、鹅卵石状的赤道部上皮细胞组织为六边形子午线行细胞的机制，主要围绕肌动蛋白细胞骨架展开。受体酪氨酸激酶EphA2的信号传导可促进F-肌动蛋白在六边形子午线行细胞顶点处的聚集，从而推动细胞的有序排列⁷^,³²⁴。肌球蛋白IIA是一种可与F-肌动蛋白结合的收缩蛋白，对维持六边形细胞形态同样具有重要作用⁸^,³²⁵^,³²⁶。长期以来，人们一直认为纤维细胞的高度有序排列是晶状体透明所必需的；然而，EphA2缺失导致的排列紊乱⁷^,³²⁴、肌球蛋白IIA突变³²⁵^,³²⁶，或老年时期形成的形态异常细胞¹³⁰等现象表明，六边形细胞排列并非透明所必需。

晶状体纤维细胞从晶状体前极延伸至后极，其长度可达数毫米，具体取决于动物物种及晶状体的大小³²⁷。通常情况下，纤维细胞的横截面仅为 4–7 µm³²⁷，这些细长的细胞通过动态的细胞间交错结构相互连接，在相邻纤维细胞之间形成一种三维“拉链”结构，如先前综述中所述³²⁸。晶状体纤维细胞的交错结构具有复杂的形态模式，随着细胞从周边新形成的纤维向成熟分化而发生改变：1）周边新形成的纤维在短侧边具有较小的突起，长侧边则具有“球与窝”状突起；2）正在经历细胞器丢失的成熟纤维细胞在短侧边具有较大的桨状结构及小型互锁突起；3）核周纤维在短侧边具有大型互锁突起，整个膜上具有“舌与槽”状交错结构；4）核内纤维在短侧边具有大型突起，整个膜上呈现球状膜形态¹³⁷^,³²⁸^,³²⁹^,³³⁰^,³³¹^,³³²^,³³³^,³³⁴^,³³⁵^,³³⁶^,³³⁷^,³³⁸^,³³⁹（图1B）。近期研究提供了直接证据，表明依赖F-actin网络的晶状体纤维细胞间交错结构对组织刚度具有重要作用¹⁷⁴，支持了一个长期存在的假说。ARVCF是黏附连接的一个组分，其缺失会导致纤维细胞交错结构异常、细胞外间隙扩大以及早发性皮质性白内障³⁴⁰。晶状体核的刚度与大小缺陷与“舌与槽”交错结构的变化以及向球状膜形态转变的延迟相关¹³¹。

比较进化模式的系统发育树图解，突出显示分支分化和物种
图3：晶状体缝合线的形成模式。每条彩色线条代表一个单一的晶状体纤维细胞。（A） 人类胚胎晶状体中的纤维细胞形成Y形缝合线。Y形缝合线在晶状体前极和后极呈镜像对称。（B） 随着人类晶状体继续发育和生长，缝合线将变得更加分支。此处为简化起见，展示了一个四分支的缝合模式。两个极之间的缝合线模式存在偏移。示意图未按比例绘制。改编自⁴⁵。请点击此处查看此图的放大版本。

晶状体的整体形状因物种而异，纤维细胞的曲率和缝合类型被认为决定了晶状体的形状³⁴¹^,³⁴²。缝合结构由前端和后端极部伸长的纤维细胞尖端相遇形成，并且两个极部之间的缝合呈镜像对称¹¹^,¹²^,¹³^,³⁴³（图3）。在小鼠晶状体中，缝合呈Y形；而在灵长类和人类晶状体中，缝合最初为Y形，随着年龄增长逐渐变得更加分支化¹¹^,¹²^,⁴⁵。有趣的是，小鼠晶状体中的Y形缝合在机械负荷移除后限制了晶状体的弹性或回弹能力，而在Eph-ephrin信号通路受干扰的基因敲除（KO）晶状体中，分支状缝合与增强的回弹性相关³⁴⁴。晶状体缝合的正常形成需要缝隙连接通讯³⁴⁵，而小鼠晶状体中与年龄相关的前部白内障则是由于缝合形成不完全所致¹³⁰。

晶状体的生物力学特性可受到多种分子、细胞和组织因素的影响，如先前综述所述¹⁶。随着年龄增长，晶状体硬度增加被认为是老视的主要成因之一³⁴⁶。在人类中，当注视远处物体时，睫状肌松弛，牵拉附着于晶状体囊膜上的悬韧带纤维，导致晶状体变扁平¹；而当聚焦近处物体时，睫状肌收缩，使悬韧带放松，晶状体随之变凸，以聚焦来自近处物体的光线¹。这一调节过程依赖于晶状体的生物力学特性、睫状肌收缩以及悬韧带张力。研究表明，随着年龄增长，睫状肌的收缩能力以及悬韧带的柔韧性和张力变化甚微或基本不变³⁴⁷^,³⁴⁸^,³⁴⁹^,³⁵⁰。多项研究提示，晶状体总体积和晶状体核体积的增大及其硬度的增加，共同导致了晶状体整体随年龄增长而硬化²⁶^,³⁵¹^,³⁵²^,³⁵³^,³⁵⁴。然而，对小鼠晶状体硬度随年龄变化的研究表明，晶状体和晶状体核的大小与整体晶状体硬度之间相关性较弱¹³⁰^,¹³²，提示其他因素在年龄相关性晶状体硬化中起重要作用。近期研究发现，细胞骨架网络的变化会影响晶状体硬度；例如，F-肌动蛋白稳定蛋白Tropomyosin 3.5的缺失会改变纤维细胞膜上F-肌动蛋白网络的组成与排列，并降低晶状体硬度¹⁷³。类似地，若干近交系野生型小鼠品系中的自发突变可导致CP49的自发敲除¹⁹²^,³⁵⁵，并伴随晶状体变软³⁵⁶^,³⁵⁷。晶状体纤维细胞膜具有异常高的胆固醇含量³⁵⁸^,³⁵⁹^,³⁶⁰^,³⁶¹^,³⁶²^,³⁶³，这可能调节膜的弹性³⁶⁴。随着年龄增长，膜内胆固醇含量的变化以及α-晶状体蛋白与纤维细胞膜的结合，被认为可能增加晶状体硬度³⁶⁵^,³⁶⁶^,³⁶⁷^,³⁶⁸^,³⁶⁹^,³⁷⁰^,³⁷¹^,³⁷²。

晶状体研究的挑战与新型方法

晶状体的三维结构为理解细胞间的排列方式以及构建合适的模型带来了挑战体外能够重现组织结构的模型。尽管利用永生化细胞或原代培养细胞已获得有关信号传导和突变蛋白定位的重要见解，但分离的晶状体上皮细胞并不具备天然晶状体上皮细胞特有的立方柱状形态，也不具有相同的基因表达或细胞骨架结构。³⁷³. 体外晶状体样体，如先前综述所述³⁷⁴ 和透镜阵列模型³⁷⁵ 分别形成类似纤维细胞的结构和形似微型晶状体的细胞团。这些模型可产生透明的、类似晶状体的结构，适用于快速药物筛选，但均无法重现正常晶状体纤维细胞的排列方式或晶状体的三维结构。目前已建立多种用于晶状体组织切片中蛋白质定位及免疫染色的实验方案，该方法仍是判断蛋白质是否在特定细胞区室中表达的最有效手段。然而，由于晶状体固定不完全，尤其是在成年晚期哺乳动物样本中，组织学切片及免疫染色操作可能较为困难。¹³⁷；而在二维切片中研究三维结构会丢失对理解细胞形态、细胞间相互作用以及蛋白质定位至关重要的细节。尽管电子显微镜（EM）仍是研究纤维细胞形态的金标准，但在EM样品中进行蛋白质定位仍然具有挑战性³⁷⁶^,³⁷⁷^,³⁷⁸. 上皮细胞单层扁平铺片的近期研究工作⁴^,⁷^,³²⁴^,³⁷³单纤维细胞染色⁸⁵^,¹⁷³^,¹⁷⁴^,³⁷⁹以及全晶状体成像⁴^,⁷^,³²⁴^,³⁴⁴^,³⁸⁰^,³⁸¹ 揭示了有关晶状体纤维中细胞间黏附、晶状体生物力学以及细胞骨架网络动态变化的重要信息。

晶状体上皮细胞与纤维细胞具有不同的功能、转录组和蛋白质组，以往对不同细胞区室的比较研究较为困难，原因是覆盖在晶状体前半球的上皮细胞仅为单层，若不合并多个样本，难以收集到足够的RNA或蛋白质。RNA提取技术、实时PCR以及自动化毛细管电泳Western blot技术的进步，使得仅从一对小鼠眼睛采集的晶状体上皮细胞样本¹³⁰^,¹³²^,³⁷³^,³⁸²，或显微解剖分离的晶状体上皮区、皮质纤维区和核纤维区³⁸³，即可进行基因和蛋白质分析。单细胞转录组学技术则实现了对斑马鱼胚胎与幼虫以及鸡胚晶状体细胞的深入分析³⁸⁴^,³⁸⁵。这些新方法为揭示在正常衰老及病理状态下维持各晶状体细胞区室功能的分子机制提供了可能。

随着该领域的进展，需要牢记小鼠的遗传背景可能在晶状体病理学³⁸⁶^,³⁸⁷和生物力学³⁵⁵^,³⁵⁶^,³⁵⁷中发挥重要作用，因此实验中使用同窝出生的对照小鼠对于数据分析至关重要。突变型和基因敲除（KO）小鼠模型为研究年龄相关性白内障以及晶状体硬度增加提供了系统支持¹³⁰^,³⁵⁶^,³⁵⁷^,³⁸⁸^,³⁸⁹^,³⁹⁰^,³⁹¹^,³⁹²^,³⁹³^,³⁹⁴^,³⁹⁵^,³⁹⁶^,³⁹⁷，由于小鼠寿命相对较短，衰老相关研究应在老年动物上进行，而不应从年轻动物的数据外推得出结论。

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结论

转录组学、蛋白质组学、成像技术以及生物力学检测技术的进步，加深了我们对晶状体生物学、生理学和病理学的理解。我们对晶状体上皮细胞和纤维细胞不同群体之间差异的认识不断扩展，这对于理解衰老过程中的变化以及蛋白质和细胞长寿的机制具有重要意义。目前，人们越来越关注开发用于预防或延缓白内障和/或老视的药物干预手段，以及白内障手术后天然晶状体再生的可能性。为预防或延缓白内障或老视而向晶状体递送药物时，需要将滴眼液配制成具有特定化学性质，以提高药物通过晶状体囊膜的递送效率，同时必须仔细研究药物在晶状体不同深度的渗透量和蓄积量³⁹⁸^,³⁹⁹^,⁴⁰⁰^,⁴⁰¹^,⁴⁰²。爬行动物中晶状体的再生已取得显著成功，有助于阐明晶状体重生所需的关键信号通路⁴⁰³^,

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披露

作者无任何利益冲突需要披露。

致谢

本工作由美国国立眼科研究所资助（项目编号 R01 EY032056，授予 CC）。作者感谢 Isaiah J. Innis 和 Gryffin M. Flowers 提出的有益意见。

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参考文献

Freddo, T. F., Chaum, E. Anatomy of the Eye and Orbit: The Clinical Essentials, 1e. , Lippincott Williams & Wilkins, a Wolters Kluwer business. (2018).
Danysh, B. P., Duncan, M. K. The lens capsule. Exp Eye Res. 88 (2), 151-164 (2009).
Zampighi, G. A., Eskandari, S., Kreman, M. Epithelial organization of the mammalian lens. Exp Eye Res. 71 (4), 415-435 (2000).
Cheng, C., Gong, X. Diverse roles of Eph/ephrin signaling in the mouse lens. PLoS One. 6 (11), e28147(2011).
Parreno, J., Cheng, C., Nowak, R. B., Fowler, V. M. The effects of mechanical strain on mouse eye lens capsule and cellular microstructure. Mol Biol Cell. 29 (16), 1963-1974 (2018).
Lovicu, F. J., Robinson, M. L. Development of the Ocular Lens. , Cambridge University Press. (2011).
Cheng, C., Ansari, M. M., Cooper, J. A., Gong, X. EphA2 and Src regulate equatorial cell morphogenesis during lens development. Development. 140 (20), 4237-4245 (2013).
Bassnett, S., Missey, H., Vucemilo, I. Molecular architecture of the lens fiber cell basal membrane complex. J Cell Sci. 112 (Pt 13), 2155-2165 (1999).
Bassnett, S., Sikic, H. The lens growth process. Prog Retin Eye Res. 60, 181-200 (2017).
Sikic, H., Shi, Y., Lubura, S., Bassnett, S. A full lifespan model of vertebrate lens growth. R Soc Open Sci. 4 (1), 160695(2017).
Kuszak, J. R. The development of lens sutures. Progress in Retinal and Eye Research. 14 (2), 567-591 (1995).
Kuszak, J. R., Mazurkiewicz, M., Zoltoski, R. Computer modeling of secondary fiber development and growth: I. Nonprimate lenses. Mol Vis. 12, 251-270 (2006).
Kuszak, J. R., Zoltoski, R. K., Tiedemann, C. E. Development of lens sutures. Int J Dev Biol. 48 (8-9), 889-902 (2004).
Kuszak, J. R. The ultrastructure of epithelial and fiber cells in the crystalline lens. Int Rev Cytol. 163, 305-350 (1995).
Kuszak, J. R., Macsai, M. S., Rae, J. L. Stereo scanning electron microscopy of the crystalline lens. Scan Electron Microsc. (Pt 3), 1415-1426 (1983).
Cheng, C. Tissue, cellular, and molecular level determinants for eye lens stiffness and elasticity. Front Ophthalmol (Lausanne). 4, 1456474(2024).
World Health Organization. World report on vision. , (2019).
Michael, R., Bron, A. J. The ageing lens and cataract: a model of normal and pathological ageing. Philos Trans R Soc Lond B Biol Sci. 366 (1568), 1278-1292 (2011).
Asbell, P. A., et al. Age-related cataract. Lancet. 365 (9459), 599-609 (2005).
Hejtmancik, J. F. Oxidative Stress in Genetic Cataract Formation. Antioxidants (Basel). 13 (11), (2024).
Shiels, A., Hejtmancik, J. F. Biology of Inherited Cataracts and Opportunities for Treatment. Annu Rev Vis Sci. 5, 123-149 (2019).
Truscott, R. J. W., Friedrich, M. G. Molecular Processes Implicated in Human Age-related Nuclear Cataract. Invest Ophthalmol Vis Sci. 60 (15), 5007-5021 (2019).
Fan, X., Monnier, V. M. Protein posttranslational modification (PTM) by glycation: Role in lens aging and age-related cataractogenesis. Exp Eye Res. 210, 108705(2021).
Budnar, P., Tangirala, R., Bakthisaran, R., Rao, C. M. Protein Aggregation and Cataract: Role of Age-related Modifications and Mutations in alpha Crystallins. Biochemistry (Mosc). 87 (3), 225-241 (2022).
Shiels, A., Hejtmancik, J. F. Inherited cataracts: Genetic mechanisms and pathways new and old. Exp Eye Res. 209, 108662(2021).
Heys, K. R., Cram, S. L., Truscott, R. J. Massive increase in the stiffness of the human lens nucleus with age: the basis for presbyopia? Mol Vis. 10, 956-963 (2004).
Glasser, A., Campbell, M. C. Biometric, optical and physical changes in the isolated human crystalline lens with age in relation to presbyopia. Vision Res. 39 (11), 1991-2015 (1999).
Weeber, H. A., et al. Dynamic mechanical properties of human lenses. Exp Eye Res. 80 (3), 425-434 (2005).
Piatigorsky, J. Lens differentiation in vertebrates. A review of cellular and molecular features. Differentiation. 19 (3), 134-153 (1981).
Gunhaga, L. The lens: a classical model of embryonic induction providing new insights into cell determination in early development. Philos Trans R Soc Lond B Biol Sci. 366 (1568), 1193-1203 (2011).
Chauhan, B. K., et al. Cdc42 and IRSp53 dependent contractile filopodia tether presumptive lens and retina to coordinate epithelial invagination. Development. 136 (21), 3657-3667 (2009).
McAvoy, J. W. Cytoplasmic processes interconnect lens placode and optic vesicle during eye morphogenesis. Exp Eye Res. 31 (5), 527-534 (1980).
Mann, I. The development of the human eye. , 3d, Grune & Stratton. (1964).
Eiraku, M., et al. Self organizing optic cup morphogenesis in three dimensional culture. Nature. 472 (7341), 51-56 (2011).
Lang, R. A., Herman, K., Reynolds, A. B., Hildebrand, J. D., Plageman, T. F. Jr p120 catenin dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis. Development. 141 (16), 3177-3187 (2014).
Plageman, T. F. Jr, et al. A Trio RhoA Shroom3 pathway is required for apical constriction and epithelial invagination. Development. 138 (23), 5177-5188 (2011).
Borges, R. M., Lamers, M. L., Forti, F. L., Santos, M. F., Yan, C. Y. Rho signaling pathway and apical constriction in the early lens placode. Genesis. 49 (5), 368-379 (2011).
Quintin, S., Gally, C., Labouesse, M. Epithelial morphogenesis in embryos: asymmetries, motors and brakes. Trends Genet. 24 (5), 221-230 (2008).
Muccioli, M., Qaisi, D., Herman, K., Plageman, T. F. Jr Lens placode planar cell polarity is dependent on Cdc42 mediated junctional contraction inhibition. Dev Biol. 412 (1), 32-43 (2016).
Houssin, N. S., Martin, J. B., Coppola, V., Yoon, S. O., Plageman, T. F. Jr Formation and contraction of multicellular actomyosin cables facilitate lens placode invagination. Dev Biol. 462 (1), 36-49 (2020).
Glucksmann, A. Cell deaths in normal vertebrate ontogeny. Biol Rev Camb Philos Soc. 26 (1), 59-86 (1951).
Ozeki, H., Ogura, Y., Hirabayashi, Y., Shimada, S. Suppression of lens stalk cell apoptosis by hyaluronic acid leads to faulty separation of the lens vesicle. Exp Eye Res. 72 (1), 63-70 (2001).
Yan, Q., Liu, J. P., Li, D. W. Apoptosis in lens development and pathology. Differentiation. 74 (5), 195-211 (2006).
Easter, S. S. Jr, Nicola, G. N. The development of vision in the zebrafish (Danio rerio). Dev Biol. 180 (2), 646-663 (1996).
Mann, I. The development of the human eye. , The University Press. (1928).
Darche, M., et al. Three dimensional characterization of developing and adult ocular vasculature in mice using in toto clearing. Communications Biology. 5 (1), 1135(2022).
Wang, Z., Liu, C. H., Huang, S., Chen, J. Assessment and Characterization of Hyaloid Vessels in Mice. J Vis Exp. (147), e59222(2019).
Hill, R. E., et al. Mouse small eye results from mutations in a paired like homeobox containing gene. Nature. 354 (6354), 522-525 (1991).
Jordan, T., et al. The human PAX6 gene is mutated in two patients with aniridia. Nat Genet. 1 (5), 328-332 (1992).
Hogan, B. L., et al. Small eyes (Sey): a homozygous lethal mutation on chromosome 2 which affects the differentiation of both lens and nasal placodes in the mouse. J Embryol Exp Morphol. 97, 95-110 (1986).
Hanson, I. M., et al. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly. Nat Genet. 6 (2), 168-173 (1994).
Grindley, J. C., Davidson, D. R., Hill, R. E. The role of Pax 6 in eye and nasal development. Development. 121 (5), 1433-1442 (1995).
Fujiwara, M., Uchida, T., Osumi Yamashita, N., Eto, K. Uchida rat (rSey): a new mutant rat with craniofacial abnormalities resembling those of the mouse Sey mutant. Differentiation. 57 (1), 31-38 (1994).
Collinson, J. M., Hill, R. E., West, J. D. Different roles for Pax6 in the optic vesicle and facial epithelium mediate early morphogenesis of the murine eye. Development. 127 (5), 945-956 (2000).
Quinn, J. C., West, J. D., Hill, R. E. Multiple functions for Pax6 in mouse eye and nasal development. Genes Dev. 10 (4), 435-446 (1996).
Ashery Padan, R., Marquardt, T., Zhou, X., Gruss, P. Pax6 activity in the lens primordium is required for lens formation and for correct placement of a single retina in the eye. Genes Dev. 14 (21), 2701-2711 (2000).
Kim, E. A., et al. Phosphorylation and transactivation of Pax6 by homeodomain interacting protein kinase 2. J Biol Chem. 281 (11), 7489-7497 (2006).
Mikkola, I., Bruun, J. A., Bjorkoy, G., Holm, T., Johansen, T. Phosphorylation of the transactivation domain of Pax6 by extracellular signal regulated kinase and p38 mitogen activated protein kinase. J Biol Chem. 274 (21), 15115-15126 (1999).
Yan, Q., et al. Sumoylation activates the transcriptional activity of Pax 6, an important transcription factor for eye and brain development. Proc Natl Acad Sci U S A. 107 (49), 21034-21039 (2010).
Yan, Q., et al. Protein phosphatase 1 modulates the function of Pax 6, a transcription factor controlling brain and eye development. J Biol Chem. 282 (19), 13954-13965 (2007).
Cvekl, A., Zhang, X. Signaling and Gene Regulatory Networks in Mammalian Lens Development. Trends Genet. 33 (10), 677-702 (2017).
Zhang, X., Friedman, A., Heaney, S., Purcell, P., Maas, R. L. Meis homeoproteins directly regulate Pax6 during vertebrate lens morphogenesis. Genes Dev. 16 (16), 2097-2107 (2002).
Dudley, A. T., Lyons, K. M., Robertson, E. J. A requirement for bone morphogenetic protein 7 during development of the mammalian kidney and eye. Genes Dev. 9 (22), 2795-2807 (1995).
Wawersik, S., et al. BMP7 acts in murine lens placode development. Dev Biol. 207 (1), 176-188 (1999).
Blixt, A., et al. A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes Dev. 14 (2), 245-254 (2000).
Brownell, I., Dirksen, M., Jamrich, M. Forkhead Foxe3 maps to the dysgenetic lens locus and is critical in lens development and differentiation. Genesis. 27 (2), 81-93 (2000).
Dimanlig, P. V., Faber, S. C., Auerbach, W., Makarenkova, H. P., Lang, R. A. The upstream ectoderm enhancer in Pax6 has an important role in lens induction. Development. 128 (22), 4415-4424 (2001).
Faber, S. C., et al. Fgf receptor signaling plays a role in lens induction. Development. 128 (22), 4425-4438 (2001).
Bavik, C., Ward, S. J., Chambon, P. Developmental abnormalities in cultured mouse embryos deprived of retinoic by inhibition of yolk sac retinol binding protein synthesis. Proc Natl Acad Sci U S A. 93 (7), 3110-3114 (1996).
Enwright, J. F. 3rd, Grainger, R. M. Altered retinoid signaling in the heads of small eye mouse embryos. Dev Biol. 221 (1), 10-22 (2000).
Lovicu, F. J., McAvoy, J. W. Growth factor regulation of lens development. Dev Biol. 280 (1), 1-14 (2005).
Schulz, M. W., Chamberlain, C. G., de Iongh, R. U., McAvoy, J. W. Acidic and basic FGF in ocular media and lens: implications for lens polarity and growth patterns. Development. 118 (1), 117-126 (1993).
Lovicu, F. J., Chamberlain, C. G., McAvoy, J. W. Differential effects of aqueous and vitreous on fiber differentiation and extracellular matrix accumulation in lens epithelial explants. Invest Ophthalmol Vis Sci. 36 (7), 1459-1469 (1995).
de Iongh, R. U., Lovicu, F. J., Chamberlain, C. G., McAvoy, J. W. Differential expression of fibroblast growth factor receptors during rat lens morphogenesis and growth. Invest Ophthalmol Vis Sci. 38 (9), 1688-1699 (1997).
de Iongh, R. U., Lovicu, F. J., Hanneken, A., Baird, A., McAvoy, J. W. FGF receptor 1 (flg) expression is correlated with fibre differentiation during rat lens morphogenesis and growth. Dev Dyn. 206 (4), 412-426 (1996).
Lovicu, F. J., Overbeek, P. A. Overlapping effects of different members of the FGF family on lens fiber differentiation in transgenic mice. Development. 125 (17), 3365-3377 (1998).
Robinson, M. L., et al. Extracellular FGF 1 acts as a lens differentiation factor in transgenic mice. Development. 121 (2), 505-514 (1995).
Robinson, M. L., et al. Disregulation of ocular morphogenesis by lens specific expression of FGF 3/int 2 in transgenic mice. Dev Biol. 198 (1), 13-31 (1998).
Faber, S. C., Robinson, M. L., Makarenkova, H. P., Lang, R. A. Bmp signaling is required for development of primary lens fiber cells. Development. 129 (15), 3727-3737 (2002).
Belecky Adams, T., et al. Pax 6, Prox 1, and Chx10 homeobox gene expression correlates with phenotypic fate of retinal precursor cells. Invest Ophthalmol Vis Sci. 38 (7), 1293-1303 (1997).
de Iongh, R. U., et al. Requirement for TGFbeta receptor signaling during terminal lens fiber differentiation. Development. 128 (20), 3995-4010 (2001).
Bassnett, S. Lens organelle degradation. Exp Eye Res. 74 (1), 1-6 (2002).
Bassnett, S. The fate of the Golgi apparatus and the endoplasmic reticulum during lens fiber cell differentiation. Invest Ophthalmol Vis Sci. 36 (9), 1793-1803 (1995).
Bassnett, S., Beebe, D. C. Coincident loss of mitochondria and nuclei during lens fiber cell differentiation. Dev Dyn. 194 (2), 85-93 (1992).
Bassnett, S., Shi, Y., Vrensen, G. F. Biological glass: structural determinants of eye lens transparency. Philos Trans R Soc Lond B Biol Sci. 366 (1568), 1250-1264 (2011).
Counis, M. F., et al. Analysis of nuclear degradation during lens cell differentiation. Cell Death Differ. 5 (4), 251-261 (1998).
Vrensen, G. F., Graw, J., De Wolf, A. Nuclear breakdown during terminal differentiation of primary lens fibres in mice: a transmission electron microscopic study. Exp Eye Res. 52 (6), 647-659 (1991).
Costello, M. J., et al. Autophagy and mitophagy participate in ocular lens organelle degradation. Exp Eye Res. 116, 141-150 (2013).
De Maria, A., Bassnett, S. DNase IIbeta distribution and activity in the mouse lens. Invest Ophthalmol Vis Sci. 48 (12), 5638-5646 (2007).
He, S., et al. Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and its denucleation. Epigenetics Chromatin. 3 (1), 21(2010).
Cui, X., et al. HSF4 regulates DLAD expression and promotes lens de nucleation. Biochim Biophys Acta. 1832 (8), 1167-1172 (2013).
Nakahara, M., et al. Degradation of nuclear DNA by DNase II like acid DNase in cortical fiber cells of mouse eye lens. FEBS J. 274 (12), 3055-3064 (2007).
Nishimoto, S., et al. Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens. Nature. 424 (6952), 1071-1074 (2003).
Chaffee, B. R., et al. Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis related nuclear disassembly. Development. 141 (17), 3388-3398 (2014).
Lyu, L., et al. Unfolded protein response associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract. FASEB J. 30 (3), 1087-1095 (2016).
Gao, M., et al. HSF4 regulates lens fiber cell differentiation by activating p53 and its downstream regulators. Cell Death Dis. 8 (10), e3082(2017).
Fujimoto, M., et al. HSF4 is required for normal cell growth and differentiation during mouse lens development. EMBO J. 23 (21), 4297-4306 (2004).
Min, J. N., Zhang, Y., Moskophidis, D., Mivechi, N. F. Unique contribution of heat shock transcription factor 4 in ocular lens development and fiber cell differentiation. Genesis. 40 (4), 205-217 (2004).
Morishita, H., et al. Organelle degradation in the lens by PLAAT phospholipases. Nature. 592 (7855), 634-638 (2021).
Capetanaki, Y., Smith, S., Heath, J. P. Overexpression of the vimentin gene in transgenic mice inhibits normal lens cell differentiation. J Cell Biol. 109 (4 Pt 1), 1653-1664 (1989).
Hamai, Y., Kuwabara, T. Early cytologic changes of Fraser cataract. An electron microscopic study. Invest Ophthalmol. 14 (7), 517-527 (1975).
Muggleton Harris, A. L., Festing, M. F., Hall, M. A gene location for the inheritance of the cataract Fraser (CatFr) mouse congenital cataract. Genet Res. 49 (3), 235-238 (1987).
Hamai, Y., Fukui, H. N., Kuwabara, T. Morphology of hereditary mouse cataract. Exp Eye Res. 18 (6), 537-546 (1974).
Takehana, M. Hereditary cataract of the Nakano mouse. Exp Eye Res. 50 (6), 671-676 (1990).
Uga, S., Kador, P. F., Kuwabara, T. Cytological study of Philly mouse cataract. Exp Eye Res. 30 (1), 79-92 (1980).
Nakamura, M., Russell, P., Carper, D. A., Inana, G., Kinoshita, J. H. Alteration of a developmentally regulated, heat stable polypeptide in the lens of the Philly mouse. Implications for cataract formation. J Biol Chem. 263 (35), 19218-19221 (1988).
Wang, K., et al. GammaD crystallin associated protein aggregation and lens fiber cell denucleation. Invest Ophthalmol Vis Sci. 48 (8), 3719-3728 (2007).
Cavalheiro, G. R., et al. N myc regulates growth and fiber cell differentiation in lens development. Dev Biol. 429 (1), 105-117 (2017).
Khillan, J. S., et al. Defects in lens fiber differentiation are linked to c mos overexpression in transgenic mice. Genes Dev. 1 (10), 1327-1335 (1987).
Lachke, S. A. RNA binding proteins and post transcriptional regulation in lens biology and cataract: Mediating spatiotemporal expression of key factors that control the cell cycle, transcription, cytoskeleton and transparency. Exp Eye Res. 214, 108889(2022).
Lachke, S. A., et al. Mutations in the RNA granule component TDRD7 cause cataract and glaucoma. Science. 331 (6024), 1571-1576 (2011).
Dash, S., Dang, C. A., Beebe, D. C., Lachke, S. A. Deficiency of the RNA binding protein caprin2 causes lens defects and features of Peters anomaly. Dev Dyn. 244 (10), 1313-1327 (2015).
Dash, S., et al. The master transcription factor SOX2, mutated in anophthalmia/microphthalmia, is post transcriptionally regulated by the conserved RNA binding protein RBM24 in vertebrate eye development. Hum Mol Genet. 29 (4), 591-604 (2020).
Siddam, A. D., et al. The RNA binding protein Celf1 post transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development. PLoS Genet. 14 (3), e1007278(2018).
Siddam, A. D., et al. High Throughput Transcriptomics of Celf1 Conditional Knockout Lens Identifies Downstream Networks Linked to Cataract Pathology. Cells. 12 (7), (2023).
Aryal, S., et al. The cataract linked RNA binding protein Celf1 post transcriptionally controls the spatiotemporal expression of the key homeodomain transcription factors Pax6 and Prox1 in lens development. Hum Genet. 139 (12), 1541-1554 (2020).
Takemoto, L., Sorensen, C. M. Protein protein interactions and lens transparency. Exp Eye Res. 87 (6), 496-501 (2008).
Oyster, C. W. The human eye : structure and function. , Sinauer Associates, Inc.. (1999).
Flaugh, S. L., Kosinski Collins, M. S., King, J. Contributions of hydrophobic domain interface interactions to the folding and stability of human gammaD crystallin. Protein Sci. 14 (3), 569-581 (2005).
Papanikolopoulou, K., et al. Formation of amyloid fibrils in vitro by human gammaD crystallin and its isolated domains. Mol Vis. 14, 81-89 (2008).
Graw, J. Genetics of crystallins: cataract and beyond. Exp Eye Res. 88 (2), 173-189 (2009).
Kosinski Collins, M. S., King, J. In vitro unfolding, refolding, and polymerization of human gammaD crystallin, a protein involved in cataract formation. Protein Sci. 12 (3), 480-490 (2003).
Horwitz, J., Bova, M. P., Ding, L. L., Haley, D. A., Stewart, P. L. Lens alpha crystallin: function and structure. Eye (Lond). 13 (Pt 3b), 403-408 (1999).
Hejtmancik, J. F., et al. Progress in Molecular Biology and Translational Science. Hejtmancik, J. F., Nickerson, J. M. 134, Academic Press. 169-201 (2015).
Bloemendal, H., et al. Ageing and vision: structure, stability and function of lens crystallins. Prog Biophys Mol Biol. 86 (3), 407-485 (2004).
Benedek, G. B. Theory of transparency of the eye. Appl Opt. 10 (3), 459-473 (1971).
Delaye, M., Tardieu, A. Short range order of crystallin proteins accounts for eye lens transparency. Nature. 302 (5907), 415-417 (1983).
Bassnett, S., Costello, M. J. The cause and consequence of fiber cell compaction in the vertebrate lens. Exp Eye Res. 156, 50-57 (2017).
Pierscionek, B. K., Regini, J. W. The gradient index lens of the eye: an opto biological synchrony. Prog Retin Eye Res. 31 (4), 332-349 (2012).
Cheng, C., et al. Age-related changes in eye lens biomechanics, morphology, refractive index and transparency. Aging (Albany NY). 11 (24), 12497-12531 (2019).
Cheng, C., et al. EphA2 Affects Development of the Eye Lens Nucleus and the Gradient of Refractive Index. Invest Ophthalmol Vis Sci. 63 (1), 2(2022).
Flowers, G. M., et al. Eph ephrin signaling affects lens growth and shape, nucleus size, and gradient refractive index in adult mice. Frontiers in Ophthalmology. 5, (2025).
Kozlowski, T. M., Kroger, R. H. H. Constant lens fiber cell thickness in fish suggests crystallin transport to denucleated cells. Vision Res. 162, 29-34 (2019).
Shestopalov, V. I., Bassnett, S. Expression of autofluorescent proteins reveals a novel protein permeable pathway between cells in the lens core. J Cell Sci. 113 (Pt 11), 1913-1921 (2000).
Shestopalov, V. I., Bassnett, S. Development of a macromolecular diffusion pathway in the lens. J Cell Sci. 116 (Pt 20), 4191-4199 (2003).
Dunia, I., et al. Structural and immunocytochemical alterations in eye lens fiber cells from Cx46 and Cx50 knockout mice. Eur J Cell Biol. 85 (8), 729-752 (2006).
Blankenship, T., Bradshaw, L., Shibata, B., Fitzgerald, P. Structural specializations emerging late in mouse lens fiber cell differentiation. Invest Ophthalmol Vis Sci. 48 (7), 3269-3276 (2007).
Lo, W. K., Reese, T. S. Multiple structural types of gap junctions in mouse lens. J Cell Sci. 106 (Pt 1), 227-235 (1993).
Baldo, G. J., et al. Gap junctional coupling in lenses from alpha(8) connexin knockout mice. J Gen Physiol. 118 (5), 447-456 (2001).
Baldo, G. J., Mathias, R. T. Spatial variations in membrane properties in the intact rat lens. Biophys J. 63 (2), 518-529 (1992).
Duncan, G., Patmore, L., Pynsent, P. B. Impedance of the amphibian lens. J Physiol. 312, 17-27 (1981).
Martinez Wittinghan, F. J., et al. Lens gap junctional coupling is modulated by connexin identity and the locus of gene expression. Invest Ophthalmol Vis Sci. 45 (10), 3629-3637 (2004).
Cheng, C., et al. Gap junction communication influences intercellular protein distribution in the lens. Exp Eye Res. 86 (6), 966-974 (2008).
Bloemendal, H. The vertebrate eye lens. Science. 197 (4299), 127-138 (1977).
van der Ouderaa, F. J., de Jong, W. W., Bloemendal, H. The amino acid sequence of the alphaA2 chain of bovine alpha crystallin. Eur J Biochem. 39 (1), 207-222 (1973).
Bloemendal, H., de Jong, W. W. Lens proteins and their genes. Prog Nucleic Acid Res Mol Biol. 41, 259-281 (1991).
Kato, K., et al. Immunoreactive alpha A crystallin in rat non lenticular tissues detected with a sensitive immunoassay method. Biochim Biophys Acta. 1080 (2), 173-180 (1991).
Srinivasan, A. N., Nagineni, C. N., Bhat, S. P. alpha A crystallin is expressed in non ocular tissues. J Biol Chem. 267 (32), 23337-23341 (1992).
Nath, M., Fort, P. E. alphaA Crystallin Mediated Neuroprotection in the Retinal Neurons Is Independent of Protein Kinase B. Front Neurosci. 16, 912757(2022).
Skeie, J. M., Mahajan, V. B. Proteomic interactions in the mouse vitreous retina complex. PLoS One. 8 (11), e82140(2013).
Ruebsam, A., et al. A specific phosphorylation regulates the protective role of alphaA crystallin in diabetes. JCI Insight. 3 (4), (2018).
Vermorken, A. J., Hilderink, J. M., van de Ven, W. J., Bloemendal, H. Lens differentiation. Crystallin synthesis in isolated epithelia from calf lenses. J Cell Biol. 76 (1), 175-183 (1978).
Boyle, D. L., Takemoto, L., Brady, J. P., Wawrousek, E. F. Morphological characterization of the Alpha A and Alpha B crystallin double knockout mouse lens. BMC Ophthalmol. 3, 3(2003).
Horwitz, J. Alpha crystallin. Exp Eye Res. 76 (2), 145-153 (2003).
Raju, M., Santhoshkumar, P., Krishna Sharma, K. Alpha crystallin derived peptides as therapeutic chaperones. Biochim Biophys Acta. 1860 (1 Pt B), 246-251 (2016).
Cheng, C., et al. Altered chaperone like activity of alpha crystallins promotes cataractogenesis. J Biol Chem. 285 (52), 41187-41193 (2010).
Aravind, P., et al. The betagamma crystallin superfamily contains a universal motif for binding calcium. Biochemistry. 48 (51), 12180-12190 (2009).
Srivastava, S. S., Mishra, A., Krishnan, B., Sharma, Y. Ca2+ binding motif of betagamma crystallins. J Biol Chem. 289 (16), 10958-10966 (2014).
Vanmarle, J., Jonges, R., Vrensen, G. F., Dewolf, A. Calcium and its localization in human lens fibres: an electron tomographic study. Exp Eye Res. 65 (1), 83-88 (1997).
Jobby, M. K., Sharma, Y. Calcium binding to lens betaB2 and betaA3 crystallins suggests that all beta crystallins are calcium binding proteins. FEBS J. 274 (16), 4135-4147 (2007).
Bergman, M. R., Deravi, L. F. Manipulating polydispersity of lens beta crystallins using divalent cations demonstrates evidence of calcium regulation. Proc Natl Acad Sci U S A. 119 (48), e2212051119(2022).
Cheng, C., Nowak, R. B., Fowler, V. M. The lens actin filament cytoskeleton: Diverse structures for complex functions. Exp Eye Res. 156, 58-71 (2017).
Quinlan, R. A., Clark, J. I. Insights into the biochemical and biophysical mechanisms mediating the longevity of the transparent optics of the eye lens. J Biol Chem. 298 (11), 102537(2022).
Song, S., et al. Functions of the intermediate filament cytoskeleton in the eye lens. J Clin Invest. 119 (7), 1837-1848 (2009).
FitzGerald, P. G. Lens intermediate filaments. Exp Eye Res. 88 (2), 165-172 (2009).
Logan, C. M., Menko, A. S. Microtubules: Evolving roles and critical cellular interactions. Exp Biol Med (Maywood). 244 (15), 1240-1254 (2019).
More, M. I., Kirsch, F. P., Rathjen, F. G. Targeted ablation of NrCAM or ankyrin B results in disorganized lens fibers leading to cataract formation. J Cell Biol. 154 (1), 187-196 (2001).
Lin, Q., et al. Genetic variations and polymorphisms in the ezrin gene are associated with age-related cataract. Mol Vis. 19, 1572-1579 (2013).
Hao, J., Kunishima, S., Guo, X., Hu, R., Gao, W. A large family with MYH9 disorder caused by E1841K mutation suffering from serious kidney and hearing impairment and cataracts. Ann Hematol. 91 (7), 1147-1148 (2012).
De Rocco, D., et al. MYH9 related disease: five novel mutations expanding the spectrum of causative mutations and confirming genotype/phenotype correlations. Eur J Med Genet. 56 (1), 7-12 (2013).
Economou, M., et al. MYH9 related disorders: report on a patient of Greek origin presenting with macroscopic hematuria and presenile cataract, caused by an R1165C mutation. J Pediatr Hematol Oncol. 34 (6), 412-415 (2012).
Saposnik, B., et al. Mutation spectrum and genotype phenotype correlations in a large French cohort of MYH9 Related Disorders. Mol Genet Genomic Med. 2 (4), 297-312 (2014).
Cheng, C., et al. Tropomyosin 3.5 protects the F-actin networks required for tissue biomechanical properties. J Cell Sci. 131 (23), (2018).
Cheng, C., et al. Tropomodulin 1 Regulation oF-actin Is Required for the Formation of Large Paddle Protrusions Between Mature Lens Fiber Cells. Invest Ophthalmol Vis Sci. 57 (10), 4084-4099 (2016).
Maddala, R., Walters, M., Brophy, P. J., Bennett, V., Rao, P. V. Ankyrin B directs membrane tethering of periaxin and is required for maintenance of lens fiber cell hexagonal shape and mechanics. Am J Physiol Cell Physiol. 310 (2), C115-C126 (2016).
Won, G. J., Fudge, D. S., Choh, V. The effects of actomyosin disruptors on the mechanical integrity of the avian crystalline lens. Mol Vis. 21, 98-109 (2015).
Kasper, M., Moll, R., Stosiek, P., Karsten, U. Patterns of cytokeratin and vimentin expression in the human eye. Histochemistry. 89 (4), 369-377 (1988).
Kasper, M., Viebahn, C. Cytokeratin expression and early lens development. Anat Embryol (Berl). 186 (3), 285-290 (1992).
Ellis, M., Alousi, S., Lawniczak, J., Maisel, H., Welsh, M. Studies on lens vimentin. Exp Eye Res. 38 (2), 195-202 (1984).
Ramaekers, F. C., Dunia, I., Dodemont, H. J., Benedetti, E. L., Bloemendal, H. Lenticular intermediate sized filaments: biosynthesis and interaction with plasma membrane. Proc Natl Acad Sci U S A. 79 (10), 3208-3212 (1982).
Ramaekers, F. C., et al. Identification of the cytoskeletal proteins in lens forming cells, a special epitheloid cell type. Exp Cell Res. 127 (2), 309-327 (1980).
FitzGerald, P. G. Immunochemical characterization of a Mr 115 lens fiber cell specific extrinsic membrane protein. Curr Eye Res. 7 (12), 1243-1253 (1988).
Ireland, M. E., et al. Up regulation of novel intermediate filament proteins in primary fiber cells: an indicator of all vertebrate lens fiber differentiation? Anat Rec. 258 (1), 25-33 (2000).
Quinlan, R. A., Stewart, M. Molecular interactions in intermediate filaments. Bioessays. 13 (11), 597-600 (1991).
Goulielmos, G., et al. Filensin and phakinin form a novel type of beaded intermediate filaments and coassemble de novo in cultured cells. J Cell Biol. 132 (4), 643-655 (1996).
Georgatos, S. D., Gounari, F., Goulielmos, G., Aebi, U. To bead or not to bead? Lens specific intermediate filaments revisited. J Cell Sci. 110 (Pt 21), 2629-2634 (1997).
Ireland, M., Maisel, H. A cytoskeletal protein unique to lens fiber cell differentiation. Exp Eye Res. 38 (6), 637-645 (1984).
Bloemendal, H., et al. Interaction of crystallins with the cytoskeletal plasma membrane complex of the bovine lens. Ciba Found Symp. 106, 177-190 (1984).
Carter, J. M., Hutcheson, A. M., Quinlan, R. A. In vitro studies on the assembly properties of the lens proteins CP49, CP115: coassembly with alpha crystallin but not with vimentin. Exp Eye Res. 60 (2), 181-192 (1995).
Chaves, J. M., Gupta, R., Srivastava, K., Srivastava, O. Human alpha A crystallin missing N terminal domain poorly complexes with filensin and phakinin. Biochem Biophys Res Commun. 494 (1-2), 402-408 (2017).
FitzGerald, P. G., Graham, D. Ultrastructural localization of alpha A crystallin to the bovine lens fiber cell cytoskeleton. Curr Eye Res. 10 (5), 417-436 (1991).
Sandilands, A., et al. Bfsp2 mutation found in mouse 129 strains causes the loss of CP49' and induces vimentin dependent changes in the lens fibre cell cytoskeleton. Exp Eye Res. 78 (4), 875-889 (2004).
Sandilands, A., et al. Knockout of the intermediate filament protein CP49 destabilises the lens fibre cell cytoskeleton and decreases lens optical quality, but does not induce cataract. Exp Eye Res. 76 (3), 385-391 (2003).
Alizadeh, A., et al. Targeted deletion of the lens fiber cell specific intermediate filament protein filensin. Invest Ophthalmol Vis Sci. 44 (12), 5252-5258 (2003).
Alizadeh, A., et al. Targeted genomic deletion of the lens specific intermediate filament protein CP49. Invest Ophthalmol Vis Sci. 43 (12), 3722-3727 (2002).
Perng, M. D., Zhang, Q., Quinlan, R. A. Insights into the beaded filament of the eye lens. Exp Cell Res. 313 (10), 2180-2188 (2007).
Muller, M., et al. Dominant cataract formation in association with a vimentin assembly disrupting mutation. Hum Mol Genet. 18 (6), 1052-1057 (2009).
Bornheim, R., et al. A dominant vimentin mutant upregulates Hsp70 and the activity of the ubiquitin proteasome system, and causes posterior cataracts in transgenic mice. J Cell Sci. 121 (Pt 22), 3737-3746 (2008).
Jakobs, P. M., et al. Autosomal dominant congenital cataract associated with a deletion mutation in the human beaded filament protein gene BFSP2. Am J Hum Genet. 66 (4), 1432-1436 (2000).
Conley, Y. P., et al. A juvenile onset, progressive cataract locus on chromosome 3q21 q22 is associated with a missense mutation in the beaded filament structural protein 2. Am J Hum Genet. 66 (4), 1426-1431 (2000).
Zhang, Q., et al. Clinical description and genome wide linkage study of Y sutural cataract and myopia in a Chinese family. Mol Vis. 10, 890-900 (2004).
Cui, X., et al. The E233del mutation in BFSP2 causes a progressive autosomal dominant congenital cataract in a Chinese family. Mol Vis. 13, 2023-2029 (2007).
Ma, X., et al. A new mutation in BFSP2 (G1091A) causes autosomal dominant congenital lamellar cataracts. Mol Vis. 14, 1906-1911 (2008).
Ramachandran, R. D., Perumalsamy, V., Hejtmancik, J. F. Autosomal recessive juvenile onset cataract associated with mutation in BFSP1. Hum Genet. 121 (3-4), 475-482 (2007).
Logan, C. M., Bowen, C. J., Menko, A. S. Functional role for stable microtubules in lens fiber cell elongation. Exp Cell Res. 362 (2), 477-488 (2018).
Basu, S., Rajakaruna, S., Reyes, B., Van Bockstaele, E., Menko, A. S. Suppression of MAPK/JNK MTORC1 signaling leads to premature loss of organelles and nuclei by autophagy during terminal differentiation of lens fiber cells. Autophagy. 10 (7), 1193-1211 (2014).
Pontoriero, G. F., et al. Co operative roles for E-cadherin and N-cadherin during lens vesicle separation and lens epithelial cell survival. Dev Biol. 326 (2), 403-417 (2009).
Leonard, M., Zhang, L., Bleaken, B. M., Menko, A. S. Distinct roles for N-cadherin linked c Src and fyn kinases in lens development. Dev Dyn. 242 (5), 469-484 (2013).
Leonard, M., et al. Modulation of N-cadherin junctions and their role as epicenters of differentiation specific actin regulation in the developing lens. Dev Biol. 349 (2), 363-377 (2011).
Maddala, R., Nagendran, T., Lang, R. A., Morozov, A., Rao, P. V. Rap1 GTPase is required for mouse lens epithelial maintenance and morphogenesis. Dev Biol. 406 (1), 74-91 (2015).
Wigle, J. T., Chowdhury, K., Gruss, P., Oliver, G. Prox1 function is crucial for mouse lens fibre elongation. Nat Genet. 21 (3), 318-322 (1999).
Xu, L., Overbeek, P. A., Reneker, L. W. Systematic analysis of E , N and P cadherin expression in mouse eye development. Exp Eye Res. 74 (6), 753-760 (2002).
Logan, C. M., et al. N-cadherin regulates signaling mechanisms required for lens fiber cell elongation and lens morphogenesis. Dev Biol. 428 (1), 118-134 (2017).
Cooper, M. A., et al. Loss of ephrin A5 function disrupts lens fiber cell packing and leads to cataract. Proc Natl Acad Sci U S A. 105 (43), 16620-16625 (2008).
Son, A. I., et al. Further analysis of the lens of ephrin A5 / mice: development of postnatal defects. Mol Vis. 19, 254-266 (2013).
Biswas, S., Son, A. I., Yu, Q., Zhou, R., Lo, W. K. Breakdown of interlocking domains may contribute to formation of membranous globules and lens opacity in ephrin A5( / ) mice. Exp Eye Res. 145, 130-139 (2016).
Maher, G. J., Black, G. C., Manson, F. D. Focus on molecules: lens intrinsic membrane protein (LIM2/MP20). Exp Eye Res. 103, 115-116 (2012).
Walker, J., Menko, A. S. Integrins in lens development and disease. Exp Eye Res. 88 (2), 216-225 (2009).
Shi, Y., et al. Further analysis of the lens phenotype in Lim2 deficient mice. Invest Ophthalmol Vis Sci. 52 (10), 7332-7339 (2011).
Mulders, J. W., et al. MP17, a fiber specific intrinsic membrane protein from mammalian eye lens. Curr Eye Res. 7 (2), 207-219 (1988).
Voorter, C. E., et al. Distribution of MP17 in isolated lens fibre membranes. Curr Eye Res. 8 (7), 697-706 (1989).
Steele, E. C. Jr, et al. Identification of a mutation in the MP19 gene, Lim2, in the cataractous mouse mutant To3. Mol Vis. 3, 5(1997).
Irum, B., et al. Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts. PLoS One. 11 (11), e0162620(2016).
Wang, X., et al. Elongated axial length and myopia related fundus changes associated with the Arg130Cys mutation in the LIM2 gene in four Chinese families with congenital cataracts. Ann Transl Med. 9 (3), 235(2021).
Berry, V., et al. A recurrent variant in LIM2 causes an isolated congenital sutural/lamellar cataract in a Japanese family. Ophthalmic Genet. 43 (5), 622-626 (2022).
Pei, R., et al. A novel mutation of LIM2 causes autosomal dominant membranous cataract in a Chinese family. Int J Ophthalmol. 13 (10), 1512-1520 (2020).
Ponnam, S. P., Ramesha, K., Tejwani, S., Matalia, J., Kannabiran, C. A missense mutation in LIM2 causes autosomal recessive congenital cataract. Mol Vis. 14, 1204-1208 (2008).
Pras, E., et al. A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family. Am J Hum Genet. 70 (5), 1363-1367 (2002).
Goyal, S., Singh, R., Singh, J. R., Vanita, V. Novel and known variants in GJA3 and LIM2 in congenital cataract families from North India. BMC Genomics. 25 (1), 31(2024).
Puk, O., Ahmad, N., Wagner, S., de Angelis, M. H., Graw, J. Microphakia and congenital cataract formation in a novel Lim2(C51R) mutant mouse. Mol Vis. 17, 1164-1171 (2011).
Dahm, R., Bramke, S., Dawczynski, J., Nagaraj, R. H., Kasper, M. Developmental aspects of galectin 3 expression in the lens. Histochem Cell Biol. 119 (3), 219-226 (2003).
Gonen, T., Donaldson, P., Kistler, J. Galectin 3 is associated with the plasma membrane of lens fiber cells. Invest Ophthalmol Vis Sci. 41 (1), 199-203 (2000).
Gonen, T., Grey, A. C., Jacobs, M. D., Donaldson, P. J., Kistler, J. MP20, the second most abundant lens membrane protein and member of the tetraspanin superfamily, joins the list of ligands of galectin 3. BMC Cell Biol. 2, 17(2001).
Barton, K. A., Hsu, C. D., Petrash, J. M. Interactions between small heat shock protein alpha crystallin and galectin related interfiber protein (GRIFIN) in the ocular lens. Biochemistry. 48 (18), 3956-3966 (2009).
Garcia Caballero, G., et al. Chicken lens development: complete signature of expression of galectins during embryogenesis and evidence for their complex formation with alpha , beta , delta , and tau crystallins, N CAM, and N-cadherin obtained by affinity chromatography. Cell Tissue Res. 379 (1), 13-35 (2020).
Garcia Caballero, G., et al. Chicken GRIFIN: binding partners, developmental course of localization and activation of its lens specific gene expression by L Maf/Pax6. Cell Tissue Res. 375 (3), 665-683 (2019).
Ogden, A. T., et al. GRIFIN, a novel lens specific protein related to the galectin family. J Biol Chem. 273 (44), 28889-28896 (1998).
Menko, A. S., Philip, N. J. Beta 1 integrins in epithelial tissues: a unique distribution in the lens. Exp Cell Res. 218 (2), 516-521 (1995).
Menko, S., Philp, N., Veneziale, B., Walker, J. Integrins and development: how might these receptors regulate differentiation of the lens. Ann N Y Acad Sci. 842, 36-41 (1998).
Walker, J. L., Menko, A. S. alpha6 Integrin is regulated with lens cell differentiation by linkage to the cytoskeleton and isoform switching. Dev Biol. 210 (2), 497-511 (1999).
Walker, J. L., Zhang, L., Zhou, J., Woolkalis, M. J., Menko, A. S. Role for alpha 6 integrin during lens development: Evidence for signaling through IGF 1R and ERK. Dev Dyn. 223 (2), 273-284 (2002).
Wederell, E. D., et al. Laminin binding integrins in rat lens morphogenesis and their regulation during fibre differentiation. Exp Eye Res. 81 (3), 326-339 (2005).
Barbour, W., et al. Expression patterns of beta1 related alpha integrin subunits in murine lens during embryonic development and wound healing. Curr Eye Res. 29 (1), 1-10 (2004).
Wu, J. E., Santoro, S. A. Complex patterns of expression suggest extensive roles for the alpha 2 beta 1 integrin in murine development. Dev Dyn. 199 (4), 292-314 (1994).
Duncan, M. K., Kozmik, Z., Cveklova, K., Piatigorsky, J., Cvekl, A. Overexpression of PAX6(5a) in lens fiber cells results in cataract and upregulation of (alpha)5(beta)1 integrin expression. J Cell Sci. 113 (Pt 18), 3173-3185 (2000).
Bassuk, J. A., et al. Disruption of the Sparc locus in mice alters the differentiation of lenticular epithelial cells and leads to cataract formation. Exp Eye Res. 68 (3), 321-331 (1999).
Gilmour, D. T., et al. Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age onset cataract formation and disruption of the lens. EMBO J. 17 (7), 1860-1870 (1998).
Kantorow, M., Horwitz, J., Carper, D. Up regulation of osteonectin/SPARC in age-related cataractous human lens epithelia. Mol Vis. 4, 17(1998).
Emerson, R. O., Sage, E. H., Ghosh, J. G., Clark, J. I. Chaperone like activity revealed in the matricellular protein SPARC. J Cell Biochem. 98 (4), 701-705 (2006).
Weaver, M. S., Sage, E. H., Yan, Q. Absence of SPARC in lens epithelial cells results in altered adhesion and extracellular matrix production in vitro. J Cell Biochem. 97 (2), 423-432 (2006).
Weaver, M. S., Workman, G., Sage, E. H. The copper binding domain of SPARC mediates cell survival in vitro via interaction with integrin beta1 and activation of integrin linked kinase. J Biol Chem. 283 (33), 22826-22837 (2008).
Yan, Q., Perdue, N., Blake, D., Sage, E. H. Absence of SPARC in murine lens epithelium leads to increased deposition of laminin 1 in lens capsule. Invest Ophthalmol Vis Sci. 46 (12), 4652-4660 (2005).
Greiling, T. M., Stone, B., Clark, J. I. Absence of SPARC leads to impaired lens circulation. Exp Eye Res. 89 (3), 416-425 (2009).
Giannone, A. A., Li, L., Sellitto, C., White, T. W. Physiological Mechanisms Regulating Lens Transport. Front Physiol. 12, 818649(2021).
Donaldson, P. J., Chen, Y., Petrova, R. S., Grey, A. C., Lim, J. C. Regulation of lens water content: Effects on the physiological optics of the lens. Prog Retin Eye Res. 95, 101152(2023).
Donaldson, P. J., Grey, A. C., Maceo Heilman, B., Lim, J. C., Vaghefi, E. The physiological optics of the lens. Prog Retin Eye Res. 56, e1-e24 (2017).
Mathias, R. T., Kistler, J., Donaldson, P. The lens circulation. J Membr Biol. 216 (1), 1-16 (2007).
Robinson, K. R., Patterson, J. W. Localization of steady currents in the lens. Curr Eye Res. 2 (12), 843-847 (1982).
Mathias, R. T., Rae, J. L., Baldo, G. J. Physiological properties of the normal lens. Physiol Rev. 77 (1), 21-50 (1997).
Gao, J., Sun, X., Yatsula, V., Wymore, R. S., Mathias, R. T. Isoform specific function and distribution of Na/K pumps in the frog lens epithelium. J Membr Biol. 178 (2), 89-101 (2000).
Alvarez, L. J., Candia, O. A., Grillone, L. R. Na+ K+ ATPase distribution in frog and bovine lenses. Curr Eye Res. 4 (2), 143-152 (1985).
Delamere, N. A., Dean, W. L. Distribution of lens sodium potassium adenosine triphosphatase. Invest Ophthalmol Vis Sci. 34 (7), 2159-2163 (1993).
Paterson, C. A. Distribution and movement of ions in the ocular lens. Doc Ophthalmol. 31 (1), 1-28 (1972).
Donaldson, P. J., Petrova, R. S., Nair, N., Chen, Y., Schey, K. L. Regulation of water flow in the ocular lens: new roles for aquaporins. J Physiol. 602 (13), 3041-3056 (2024).
Goodenough, D. A. The crystalline lens. A system networked by gap junctional intercellular communication. Semin Cell Biol. 3 (1), 49-58 (1992).
Mathias, R. T., White, T. W., Gong, X. Lens gap junctions in growth, differentiation, and homeostasis. Physiol Rev. 90 (1), 179-206 (2010).
Beyer, E. C., Kistler, J., Paul, D. L., Goodenough, D. A. Antisera directed against connexin43 peptides react with a 43 kD protein localized to gap junctions in myocardium and other tissues. J Cell Biol. 108 (2), 595-605 (1989).
Gao, Y., Spray, D. C. Structural changes in lenses of mice lacking the gap junction protein connexin43. Invest Ophthalmol Vis Sci. 39 (7), 1198-1209 (1998).
Rong, P., et al. Disruption of Gja8 (alpha8 connexin) in mice leads to microphthalmia associated with retardation of lens growth and lens fiber maturation. Development. 129 (1), 167-174 (2002).
Puk, O., et al. Mutation in a novel connexin like gene (Gjf1) in the mouse affects early lens development and causes a variable small eye phenotype. Invest Ophthalmol Vis Sci. 49 (4), 1525-1532 (2008).
Sonntag, S., et al. Mouse lens connexin23 (Gje1) does not form functional gap junction channels but causes enhanced ATP release from HeLa cells. Eur J Cell Biol. 88 (2), 65-77 (2009).
Bassnett, S., Wilmarth, P. A., David, L. L. The membrane proteome of the mouse lens fiber cell. Mol Vis. 15, 2448-2463 (2009).
Wang, Z., Han, J., David, L. L., Schey, K. L. Proteomics and phosphoproteomics analysis of human lens fiber cell membranes. Invest Ophthalmol Vis Sci. 54 (2), 1135-1143 (2013).
Berthoud, V. M., et al. Connexin23 deletion does not affect lens transparency. Exp Eye Res. 146, 283-288 (2016).
Fleishman, S. J., Unger, V. M., Yeager, M., Ben Tal, N. A Calpha model for the transmembrane alpha helices of gap junction intercellular channels. Mol Cell. 15 (6), 879-888 (2004).
Unger, V. M., Kumar, N. M., Gilula, N. B., Yeager, M. Three dimensional structure of a recombinant gap junction membrane channel. Science. 283 (5405), 1176-1180 (1999).
Hu, Z., Riquelme, M. A., Gu, S., Jiang, J. X. Regulation of Connexin Gap Junctions and Hemichannels by Calcium and Calcium Binding Protein Calmodulin. Int J Mol Sci. 21 (21), (2020).
Quan, Y., Du, Y., Tong, Y., Gu, S., Jiang, J. X. Connexin Gap Junctions and Hemichannels in Modulating Lens Redox Homeostasis and Oxidative Stress in Cataractogenesis. Antioxidants (Basel). 10 (9), (2021).
Ebihara, L., Korzyukov, Y., Kothari, S., Tong, J. J. Cx46 hemichannels contribute to the sodium leak conductance in lens fiber cells. Am J Physiol Cell Physiol. 306 (5), C506-C513 (2014).
Liu, J., et al. Mechanosensitive collaboration between integrins and connexins allows nutrient and antioxidant transport into the lens. J Cell Biol. 219 (12), (2020).
Tong, Y., et al. Mechano activated connexin hemichannels and glutathione transport protect lens fiber cells against oxidative insults. Redox Biol. 73, 103216(2024).
Wang, G., Quan, Y., Ma, B., Gu, S., Jiang, J. X. Mechano activated connexin hemichannels mediate intercellular glutathione transport and support lens redox homeostasis. Redox Biol. 85, 103767(2025).
Shi, W., Riquelme, M. A., Gu, S., Jiang, J. X. Connexin hemichannels mediate glutathione transport and protect lens fiber cells from oxidative stress. J Cell Sci. 131 (6), (2018).
Ramachandran, S., Xie, L. H., John, S. A., Subramaniam, S., Lal, R. A novel role for connexin hemichannel in oxidative stress and smoking induced cell injury. PLoS One. 2 (8), e712(2007).
Quan, Y., Du, Y., Wu, C., Gu, S., Jiang, J. X. Connexin hemichannels regulate redox potential via metabolite exchange and protect lens against cellular oxidative damage. Redox Biol. 46, 102102(2021).
Quan, Y., Du, Y., Wu, C., Gu, S., Jiang, J. X. Data on Connexin 43 hemichannels regulation of cellular redox in lens. Data Brief. 39, 107572(2021).
Ren, Q., et al. Cataract causing mutation of human connexin 46 impairs gap junction, but increases hemichannel function and cell death. PLoS One. 8 (9), e74732(2013).
Siller Jackson, A. J., et al. Adaptation of connexin 43 hemichannel prostaglandin release to mechanical loading. J Biol Chem. 283 (39), 26374-26382 (2008).
Cheng, C., et al. Lens ion homeostasis relies on the assembly and/or stability of large connexin 46 gap junction plaques on the broad sides of differentiating fiber cells. Am J Physiol Cell Physiol. 308 (10), C835-C847 (2015).
Gong, X., et al. Disruption of alpha3 connexin gene leads to proteolysis and cataractogenesis in mice. Cell. 91 (6), 833-843 (1997).
Gong, X., Baldo, G. J., Kumar, N. M., Gilula, N. B., Mathias, R. T. Gap junctional coupling in lenses lacking alpha3 connexin. Proc Natl Acad Sci U S A. 95 (26), 15303-15308 (1998).
White, T. W., Goodenough, D. A., Paul, D. L. Targeted ablation of connexin50 in mice results in microphthalmia and zonular pulverulent cataracts. J Cell Biol. 143 (3), 815-825 (1998).
Sellitto, C., Li, L., White, T. W. Connexin50 is essential for normal postnatal lens cell proliferation. Invest Ophthalmol Vis Sci. 45 (9), 3196-3202 (2004).
White, T. W. Unique and redundant connexin contributions to lens development. Science. 295 (5553), 319-320 (2002).
Li, L., et al. Connexin mediated cataract prevention in mice. PLoS One. 5 (9), (2010).
Schey, K. L., et al. Lens Aquaporins in Health and Disease: Location is Everything! Front Physiol. 13, 882550(2022).
Schey, K. L., Petrova, R. S., Gletten, R. B., Donaldson, P. J. The Role of Aquaporins in Ocular Lens Homeostasis. Int J Mol Sci. 18 (12), (2017).
Gao, J., et al. Lens intracellular hydrostatic pressure is generated by the circulation of sodium and modulated by gap junction coupling. J Gen Physiol. 137 (6), 507-520 (2011).
Gao, J., Sun, X., White, T. W., Delamere, N. A., Mathias, R. T. Feedback Regulation of Intracellular Hydrostatic Pressure in Surface Cells of the Lens. Biophys J. 109 (9), 1830-1839 (2015).
Shahidullah, M., et al. TRPV1 activation stimulates NKCC1 and increases hydrostatic pressure in the mouse lens. Am J Physiol Cell Physiol. 318 (5), C969-C980 (2020).
Petrova, R. S., et al. Modulation of Membrane Trafficking of AQP5 in the Lens in Response to Changes in Zonular Tension Is Mediated by the Mechanosensitive Channel TRPV1. Int J Mol Sci. 24 (10), (2023).
Chen, Y., Petrova, R. S., Qiu, C., Donaldson, P. J. Intracellular hydrostatic pressure regulation in the bovine lens: a role in the regulation of lens optics? Am J Physiol Regul Integr Comp Physiol. 322 (3), R263-R279 (2022).
Donaldson, P. J., Musil, L. S., Mathias, R. T. Point: A critical appraisal of the lens circulation model an experimental paradigm for understanding the maintenance of lens transparency? Invest Ophthalmol Vis Sci. 51 (5), 2303-2306 (2010).
Merriman Smith, B. R., Krushinsky, A., Kistler, J., Donaldson, P. J. Expression patterns for glucose transporters GLUT1 and GLUT3 in the normal rat lens and in models of diabetic cataract. Invest Ophthalmol Vis Sci. 44 (8), 3458-3466 (2003).
Merriman Smith, R., Donaldson, P., Kistler, J. Differential expression of facilitative glucose transporters GLUT1 and GLUT3 in the lens. Invest Ophthalmol Vis Sci. 40 (13), 3224-3230 (1999).
Zahraei, A., et al. Mapping Glucose Uptake, Transport and Metabolism in the Bovine Lens Cortex. Front Physiol. 13, 901407(2022).
Lim, J. C., Perwick, R. D., Li, B., Donaldson, P. J. Comparison of the expression and spatial localization of glucose transporters in the rat, bovine and human lens. Exp Eye Res. 161, 193-204 (2017).
Swarup, A., et al. Deletion of GLUT1 in mouse lens epithelium leads to cataract formation. Exp Eye Res. 172, 45-53 (2018).
Reddy, V. N. Metabolism of glutathione in the lens. Exp Eye Res. 11 (3), 310-328 (1971).
Truscott, R. J. Age-related nuclear cataract oxidation is the key. Exp Eye Res. 80 (5), 709-725 (2005).
Kannan, R., Yi, J. R., Zlokovic, B. V., Kaplowitz, N. Molecular characterization of a reduced glutathione transporter in the lens. Invest Ophthalmol Vis Sci. 36 (9), 1785-1792 (1995).
Mackic, J. B., et al. Transport of circulating reduced glutathione at the basolateral side of the anterior lens epithelium: physiologic importance and manipulations. Exp Eye Res. 62 (1), 29-37 (1996).
Li, B., Li, L., Donaldson, P. J., Lim, J. C. Dynamic regulation of GSH synthesis and uptake pathways in the rat lens epithelium. Exp Eye Res. 90 (2), 300-307 (2010).
Lim, J., Li, L., Jacobs, M. D., Kistler, J., Donaldson, P. J. Mapping of glutathione and its precursor amino acids reveals a role for GLYT2 in glycine uptake in the lens core. Invest Ophthalmol Vis Sci. 48 (11), 5142-5151 (2007).
Li, L., Lim, J., Jacobs, M. D., Kistler, J., Donaldson, P. J. Regional differences in cystine accumulation point to a sutural delivery pathway to the lens core. Invest Ophthalmol Vis Sci. 48 (3), 1253-1260 (2007).
Rathbun, W. B. Activity of glutathione synthesis enzymes in the rhesus monkey lens related to age: a model for the human lens. Curr Eye Res. 5 (2), 161-166 (1986).
Sethna, S. S., Holleschau, A. M., Rathbun, W. B. Activity of glutathione synthesis enzymes in human lens related to age. Curr Eye Res. 2 (11), 735-742 (1982).
Giblin, F. J., et al. Nuclear light scattering, disulfide formation and membrane damage in lenses of older guinea pigs treated with hyperbaric oxygen. Exp Eye Res. 60 (3), 219-235 (1995).
Padgaonkar, V. A., et al. Hyperbaric oxygen in vivo accelerates the loss of cytoskeletal proteins and MIP26 in guinea pig lens nucleus. Exp Eye Res. 68 (4), 493-504 (1999).
Padgaonkar, V., Giblin, F. J., Reddy, V. N. Disulfide cross linking of urea insoluble proteins in rabbit lenses treated with hyperbaric oxygen. Exp Eye Res. 49 (5), 887-899 (1989).
Lou, M. F., Dickerson, J. E. Jr Protein thiol mixed disulfides in human lens. Exp Eye Res. 55 (6), 889-896 (1992).
Wei, Z., et al. Aging lens epithelium is susceptible to ferroptosis. Free Radic Biol Med. 167, 94-108 (2021).
Wei, Z., et al. Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract. Proc Natl Acad Sci U S A. 121 (48), e2407842121(2024).
Cheng, C., Fowler, V. M., Gong, X. EphA2 and ephrin A5 are not a receptor ligand pair in the ocular lens. Exp Eye Res. 162, 9-17 (2017).
Islam, S. T., Cheheltani, S., Cheng, C., Fowler, V. M. Disease related non muscle myosin IIA D1424N rod domain mutation, but not R702C motor domain mutation, disrupts mouse ocular lens fiber cell alignment and hexagonal packing. Cytoskeleton (Hoboken). 81 (12), 789-805 (2024).
Islam, S. T., Cheng, C., Parreno, J., Fowler, V. M. Nonmuscle Myosin IIA Regulates the Precise Alignment of Hexagonal Eye Lens Epithelial Cells During Fiber Cell Formation and Differentiation. Invest Ophthalmol Vis Sci. 64 (4), 20(2023).
Forrester, J. V., Dick, A. D., McMenamin, P. G., Roberts, F., Pearlman, E. The Eye (Fourth Edition). Forrester, J. V. , W.B. Saunders. 1-102.e102 (2016).
D’Amore, P. A. Encyclopedia of the Eye (Second Edition). , Elsevier. 514-520 (2025).
Vrensen, G. F. Aging of the human eye lens a morphological point of view. Comp Biochem Physiol A Physiol. 111 (4), 519-532 (1995).
Vrensen, G. F., Duindam, H. J. Maturation of fiber membranes in the human eye lens. Ultrastructural and Raman microspectroscopic observations. Ophthalmic Res. 27 Suppl 1, 78-85 (1995).
Willekens, B., Vrensen, G. The three dimensional organization of lens fibers in the rabbit. A scanning electron microscopic reinvestigation. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 216 (4), 275-289 (1981).
Willekens, B., Vrensen, G. The three dimensional organization of lens fibers in the rhesus monkey. Graefes Arch Clin Exp Ophthalmol. 219 (3), 112-120 (1982).
Willekens, B., Vrensen, G. Lens fiber organization in four avian species: a scanning electron microscopic study. Tissue Cell. 17 (3), 359-377 (1985).
Lo, W. K., et al. Aquaporin 0 targets interlocking domains to control the integrity and transparency of the eye lens. Invest Ophthalmol Vis Sci. 55 (3), 1202-1212 (2014).
Lo, W. K., Harding, C. V. Square arrays and their role in ridge formation in human lens fibers. J Ultrastruct Res. 86 (3), 228-245 (1984).
Kistler, J., et al. Membrane interlocking domains in the lens. Invest Ophthalmol Vis Sci. 27 (10), 1527-1534 (1986).
Dickson, D. H., Crock, G. W. Interlocking patterns on primate lens fibers. Invest Ophthalmol. 11 (10), 809-815 (1972).
Kuszak, J., Alcala, J., Maisel, H. The surface morphology of embryonic and adult chick lens fiber cells. Am J Anat. 159 (4), 395-410 (1980).
Kuwabara, T. The maturation of the lens cell: a morphologic study. Exp Eye Res. 20 (5), 427-443 (1975).
Martin, J. B., et al. Arvcf Dependent Adherens Junction Stability is Required to Prevent Age-related Cortical Cataracts. Front Cell Dev Biol. 10, 840129(2022).
Chen, Y., Stump, R. J., Lovicu, F. J., Shimono, A., McAvoy, J. W. Wnt signaling is required for organization of the lens fiber cell cytoskeleton and development of lens three dimensional architecture. Dev Biol. 324 (1), 161-176 (2008).
Sugiyama, Y., et al. Concave to convex curve conversion of fiber cells correlates with Y shaped suture formation at the poles of the rodent lens. Exp Eye Res. 248, 110066(2024).
Kuszak, J. R., Sivak, J. G., Weerheim, J. A. Lens optical quality is a direct function of lens sutural architecture. Invest Ophthalmol Vis Sci. 32 (7), 2119-2129 (1991).
Cheng, C. EphA2 and Ephrin A5 Guide Eye Lens Suture Alignment and Influence Whole Lens Resilience. Invest Ophthalmol Vis Sci. 62 (15), 3(2021).
Xia, C. H., et al. Absence of alpha3 (Cx46) and alpha8 (Cx50) connexins leads to cataracts by affecting lens inner fiber cells. Exp Eye Res. 83 (3), 688-696 (2006).
BEERS, A. P. A., van der HEIJDE, G. L. Age-related Changes in the Accommodation Mechanism. Optometry and Vision Science. 73 (4), 235-242 (1996).
van Alphen, G. W., Graebel, W. P. Elasticity of tissues involved in accommodation. Vision Res. 31 (7-8), 1417-1438 (1991).
Fisher, R. F. The ciliary body in accommodation. Trans Ophthalmol Soc U K (1962). 105 (Pt 2), 208-219 (1986).
Graebel, W. P., van Alphen, G. W. H. M. The Elasticity of Sclera and Choroid of the Human Eye, and Its Implications on Scleral Rigidity and Accommodation. Journal of Biomechanical Engineering. 99 (4), 203-208 (1977).
Tamm, S., Tamm, E., Rohen, J. W. Age-related changes of the human ciliary muscle. A quantitative morphometric study. Mech Ageing Dev. 62 (2), 209-221 (1992).
Scarcelli, G., Kim, P., Yun, S. H. In vivo measurement of age-related stiffening in the crystalline lens by Brillouin optical microscopy. Biophys J. 101 (6), 1539-1545 (2011).
Zhou, H., Yan, H., Yan, W., Wang, X., Li, Q. In vivo ultraosound elastographic evaluation of the age-related change of human lens nuclear stiffness. BMC Ophthalmol. 20 (1), 135(2020).
Hermans, E., Dubbelman, M., van der Heijde, R., Heethaar, R. The shape of the human lens nucleus with accommodation. J Vis. 7 (10), 16.1-10 (2007).
Fisher, R. F., Pettet, B. E. Presbyopia and the water content of the human crystalline lens. J Physiol. 234 (2), 443-447 (1973).
Alizadeh, A., et al. Characterization of a mutation in the lens specific CP49 in the 129 strain of mouse. Invest Ophthalmol Vis Sci. 45 (3), 884-891 (2004).
Fudge, D. S., et al. Intermediate filaments regulate tissue size and stiffness in the murine lens. Invest Ophthalmol Vis Sci. 52 (6), 3860-3867 (2011).
Gokhin, D. S., et al. Tmod1 and CP49 synergize to control the fiber cell geometry, transparency, and mechanical stiffness of the mouse lens. PLoS One. 7 (11), e48734(2012).
Duindam, J. J., Vrensen, G. F., Otto, C., Greve, J. Aging affects the conformation of cholesterol in the human eye lens. Ophthalmic Res. 28 Suppl 1, 86-91 (1996).
Li, L. K., So, L., Spector, A. Age dependent changes in the distribution and concentration of human lens cholesterol and phospholipids. Biochim Biophys Acta. 917 (1), 112-120 (1987).
Mainali, L., Raguz, M., O'Brien, W. J., Subczynski, W. K. Changes in the Properties and Organization of Human Lens Lipid Membranes Occurring with Age. Curr Eye Res. 42 (5), 721-731 (2017).
Truscott, R. J. Age-related nuclear cataract: a lens transport problem. Ophthalmic Res. 32 (5), 185-194 (2000).
Subczynski, W. K., Raguz, M., Widomska, J., Mainali, L., Konovalov, A. Functions of cholesterol and the cholesterol bilayer domain specific to the fiber cell plasma membrane of the eye lens. J Membr Biol. 245 (1), 51-68 (2012).
Widomska, J., Subczynski, W. K. Why Is Very High Cholesterol Content Beneficial for the Eye Lens but Negative for Other Organs? Nutrients. 11 (5), (2019).
Khadka, N. K., Mortimer, M. F., Marosvari, M., Timsina, R., Mainali, L. Membrane elasticity modulated by cholesterol in model of porcine eye lens lipid membrane. Exp Eye Res. 220, 109131(2022).
Bracchi, P. G., Carta, F., Fasella, P., Maraini, G. Selective binding of aged alpha crystallin to lens fibre ghosts. Exp Eye Res. 12 (1), 151-154 (1971).
Maraini, G., Fasella, P. Reversible binding of soluble lens proteins to lens fibre ghosts. Exp Eye Res. 10 (1), 133-139 (1970).
Broekhuyse, R. M., Kuhlmann, E. D. Lens membranes. IV. Preparative isolation and characterization of membranes and various membrane proteins from calf lens. Exp Eye Res. 26 (3), 305-320 (1978).
Friedrich, M. G., Truscott, R. J. Large scale binding of alpha crystallin to cell membranes of aged normal human lenses: a phenomenon that can be induced by mild thermal stress. Invest Ophthalmol Vis Sci. 51 (10), 5145-5152 (2010).
Khadka, N. K., Timsina, R., Mainali, L. An AFM Approach Applied in a Study of alpha Crystallin Membrane Association: New Insights into Lens Hardening and Presbyopia Development. Membranes (Basel). 12 (5), (2022).
Timsina, R., Khadka, N. K., Maldonado, D., Mainali, L. Interaction of alpha crystallin with four major phospholipids of eye lens membranes. Exp Eye Res. 202, 108337(2021).
Timsina, R., Mainali, L. Association of Alpha Crystallin with Fiber Cell Plasma Membrane of the Eye Lens Accompanied by Light Scattering and Cataract Formation. Membranes (Basel). 11 (6), (2021).
Timsina, R., Trossi Torres, G., O'Dell, M., Khadka, N. K., Mainali, L. Cholesterol and cholesterol bilayer domains inhibit binding of alpha crystallin to the membranes made of the major phospholipids of eye lens fiber cell plasma membranes. Exp Eye Res. 206, 108544(2021).
Parreno, J., et al. Methodologies to unlock the molecular expression and cellular structure of ocular lens epithelial cells. Front Cell Dev Biol. 10, 983178(2022).
Cvekl, A., Camerino, M. J. Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology. Cells. 11 (21), (2022).
Murphy, P., et al. Light focusing human micro lenses generated from pluripotent stem cells model lens development and drug induced cataract in vitro. Development. 145 (1), (2018).
Goldberg, M. W. High Resolution Scanning Electron Microscopy and Immuno Gold Labeling of the Nuclear Lamina and Nuclear Pore Complex. Methods Mol Biol. 1411, 441-459 (2016).
Goldberg, M. W., Fiserova, J. Immunogold Labeling for Scanning Electron Microscopy. Methods Mol Biol. 1474, 309-325 (2016).
Hermann, R., Walther, P., Muller, M. Immunogold labeling in scanning electron microscopy. Histochem Cell Biol. 106 (1), 31-39 (1996).
Vu, M. P., Cheng, C. Preparation and Immunofluorescence Staining of Bundles and Single Fiber Cells from the Cortex and Nucleus of the Eye Lens. J Vis Exp. (196), e65638(2023).
Emin, G., et al. Whole Mount Imaging to Visualize and Quantify Peripheral Lens Structure, Cell Morphology, and Organization. J Vis Exp. (203), e66017(2024).
Zhou, Y., Shiels, A. Epha2 and Efna5 participate in lens cell pattern formation. Differentiation. 102, 1-9 (2018).
Huynh, P. N., Cheng, C. Spatial temporal comparison of Eph/Ephrin gene expression in ocular lenses from aging and knockout mice. Front Ophthalmol (Lausanne). 4, 1410860(2024).
Disatham, J., et al. Lens differentiation is characterized by stage specific changes in chromatin accessibility correlating with differentiation state specific gene expression. Dev Biol. 453 (1), 86-104 (2019).
Farnsworth, D. R., Posner, M., Miller, A. C. Single cell transcriptomics of the developing zebrafish lens and identification of putative controllers of lens development. Exp Eye Res. 206, 108535(2021).
Tangeman, J. A., et al. Integrated single cell multiomics uncovers foundational regulatory mechanisms of lens development and pathology. Development. 151 (1), (2024).
Xia, C. H., et al. Periaxin gene variants are linked to age-related cataracts in Cx46 deficient lenses. Commun Biol. 8 (1), 1356(2025).
Gong, X., Agopian, K., Kumar, N. M., Gilula, N. B. Genetic factors influence cataract formation in alpha 3 connexin knockout mice. Dev Genet. 24 (1-2), 27-32 (1999).
Baradia, H., Nikahd, N., Glasser, A. Mouse lens stiffness measurements. Exp Eye Res. 91 (2), 300-307 (2010).
Sindhu Kumari, S., et al. Role of Aquaporin 0 in lens biomechanics. Biochem Biophys Res Commun. 462 (4), 339-345 (2015).
Cheng, C., Gokhin, D. S., Nowak, R. B., Fowler, V. M. Sequential Application of Glass Coverslips to Assess the Compressive Stiffness of the Mouse Lens: Strain and Morphometric Analyses. J Vis Exp. (111), e53986(2016).
Wolf, N. S., Li, Y., Pendergrass, W., Schmeider, C., Turturro, A. Normal mouse and rat strains as models for age-related cataract and the effect of caloric restriction on its development. Exp Eye Res. 70 (5), 683-692 (2000).
Martin Montalvo, A., et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 4, 2192(2013).
Pearson, K. J., et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8 (2), 157-168 (2008).
Pendergrass, W., Penn, P., Possin, D., Wolf, N. Accumulation of DNA, nuclear and mitochondrial debris, and ROS at sites of age-related cortical cataract in mice. Invest Ophthalmol Vis Sci. 46 (12), 4661-4670 (2005).
Pendergrass, W. R., Penn, P. E., Li, J., Wolf, N. S. Age-related telomere shortening occurs in lens epithelium from old rats and is slowed by caloric restriction. Exp Eye Res. 73 (2), 221-228 (2001).
Schriner, S. E., et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 308 (5730), 1909-1911 (2005).
Wolf, N., et al. Age-related cataract progression in five mouse models for anti oxidant protection or hormonal influence. Exp Eye Res. 81 (3), 276-285 (2005).
Panja, S., et al. Aggrelyte 2 promotes protein solubility and decreases lens stiffness through lysine acetylation and disulfide reduction: Implications for treating presbyopia. Aging Cell. 22 (4), e13797(2023).
Panja, S., Nam, M. H., Gaikwad, H., Rankenberg, J., Nagaraj, R. H. Topical ocular application of aggrelyte 2A reduces lens stiffness in mice. Frontiers in Ophthalmology. 3, (2023).
Kador, P. F., Guo, C., Kawada, H., Randazzo, J., Blessing, K. Topical nutraceutical Optixcare EH ameliorates experimental ocular oxidative stress in rats. J Ocul Pharmacol Ther. 30 (7), 593-602 (2014).
Kador, P. F., Webb, T. R., Bras, D., Ketring, K., Wyman, M. Topical KINOSTAT ameliorates the clinical development and progression of cataracts in dogs with diabetes mellitus. Vet Ophthalmol. 13 (6), 363-368 (2010).
Kador, P. F., Wyman, M., Oates, P. J. Aldose reductase, ocular diabetic complications and the development of topical Kinostat((R)). Prog Retin Eye Res. 54, 1-29 (2016).
Maden, M. Salamanders as Key Models for Development and Regeneration Research. Methods Mol Biol. 2562, 1-23 (2023).
Grogg, M. W., Call, M. K., Tsonis, P. A. Signaling during lens regeneration. Semin Cell Dev Biol. 17 (6), 753-758 (2006).
Tsonis, P. A., Makarev, E. On dorsal/ventral specific genes in the iris during lens regeneration. Cell Mol Life Sci. 65 (1), 41-44 (2008).
Kha, C. X., Son, P. H., Lauper, J., Tseng, K. A. A model for investigating developmental eye repair in Xenopus laevis. Exp Eye Res. 169, 38-47 (2018).
Gwon, A. E., Gruber, L. J., Mundwiler, K. E. A histologic study of lens regeneration in aphakic rabbits. Invest Ophthalmol Vis Sci. 31 (3), 540-547 (1990).
Gwon, A., Gruber, L. J., Mantras, C. Restoring lens capsule integrity enhances lens regeneration in New Zealand albino rabbits and cats. J Cataract Refract Surg. 19 (6), 735-746 (1993).
Medvedovic, M., Tomlinson, C. R., Call, M. K., Grogg, M., Tsonis, P. A. Gene expression and discovery during lens regeneration in mouse: regulation of epithelial to mesenchymal transition and lens differentiation. Mol Vis. 12, 422-440 (2006).
Call, M. K., Grogg, M. W., Del Rio Tsonis, K., Tsonis, P. A. Lens regeneration in mice: implications in cataracts. Exp Eye Res. 78 (2), 297-299 (2004).
Kuszak, J. R., Brown, H. G. Embryology and anatomy of the crystallin lens. , W.B. Saunders. 82-96 (1994).

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聚焦哺乳动物眼晶状体：发育、解剖、生理、透明性、生物力学及与年龄相关的问题

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