live-imaging-characterization-microglia-dynamics-interactions-with

Live Imaging and Characterization of Microglia Dynamics and Interactions with Synapses in Diseased Murine Retina

Microglia are the resident macrophages of the central nervous system (CNS) that respond to tissue infection and injury. In addition to their role in ...

University of California, San Francisco

The formation of the vertebrate optic cup is a morphogenetic event initiated after the optic vesicle contacts the overlying surface/pre-lens ectoderm. Placodes form in both the optic neuroepithelium and lens ectoderm. Subsequently, both placodes invaginate to form the definitive optic cup and lens, respectively. We examined the role of the lens tissue in inducing and/or maintaining optic cup invagination in ovo. Lens tissue was surgically removed at various stages of development, from pre-lens ectoderm stages to invaginating lens placode. Removal of the pre-lens ectoderm resulted in persistent optic vesicles that initiated neural retinal differentiation but failed to invaginate. In striking contrast, ablation of the lens placode gave rise to optic vesicles that underwent invagination and formed the optic cup. The results suggest that: (1) the optic vesicle neuroepithelium requires a temporally specific association with pre-lens ectoderm in order to undergo optic cup morphogenesis; and (2) the optic cup can form in the absence of lens formation. If ectopic BMP is added, a neural retina does not develop and optic cup morphogenesis fails, although lens formation appears normal. FGF-induced neural retina differentiation in the absence of the pre-lens ectoderm is not sufficient to create an optic cup. We hypothesize the presence of a signal coming from the pre-lens ectoderm that induces the optic vesicle to form an optic cup.

Optic cup morphogenesis requires pre-lens ectoderm but not lens differentiation.

&#x51E0;&#x4E4E;&#x5B8C;&#x5168;&#x662F;&#x5728;&#x513F;&#x7AE5;&#xFF0C;&#x51FA;&#x73B0;&#x5F25;&#x6F2B;&#x6027;&#x5185;&#x5728;&#x6865;&#x8111;&#x80F6;&#x8D28;&#x7624;&#x548C;&#x6CBB;&#x7597;&#x7684;&#x8FDB;&#x5C55;&#xFF0C;&#x5C3D;&#x7BA1;&#x591A;&#x6570;&#x75C5;&#x4EBA;&#x521D;&#x6B65;&#x8BCA;&#x65AD;&#x540E; 2 &#x5E74;&#x5185;&#x6B7B;&#x4EA1;&#x3002;&#x7531;&#x4E8E;&#x5176;&#x6D78;&#x6DA6;&#x6027;&#x8D28;&#x548C;&#x5927;&#x8111;&#x529F;&#x80FD;&#x533A;&#x4E2D;&#x7684;&#x89E3;&#x5256;&#x4F4D;&#x7F6E;&#xFF0C;&#x6700;&#x6865;&#x8111;&#x80F6;&#x8D28;&#x7624;&#x88AB;&#x89C6;&#x4E3A;&#x65E0;&#x624B;&#x672F;&#x6D3B;&#x68C0;&#x3002;&#x76F8;&#x5E94;&#x7F3A;&#x4E4F;&#x7EC4;&#x7EC7;&#x6837;&#x672C;&#x5DF2;&#x5BFC;&#x81F4;&#x4E0E;&#x8111;&#x6865;&#x80F6;&#x8D28;&#x7624;&#xFF0C;&#x76F8;&#x5173;&#x8054;&#x7684;&#x57FA;&#x7840;&#x9057;&#x4F20;&#x548C;&#x5206;&#x5B50;&#x751F;&#x7269;&#x5B66;&#x5F02;&#x5E38;&#x7684;&#x4E86;&#x89E3;&#x6709;&#x9650;&#xFF0C;&#x662F;&#x6709;&#x9488;&#x5BF9;&#x6027;&#x7684;&#x6CBB;&#x7597;&#x5242;&#xFF0C;&#x8FD9;&#x4E9B;&#x80BF;&#x7624;&#x7684;&#x4E34;&#x5E8A;&#x524D;&#x6D4B;&#x8BD5;&#x7684;&#x5B9E;&#x8D28;&#x6027;&#x969C;&#x788D;&#x3002;&#x6211;&#x4EEC;&#x5EFA;&#x7ACB;&#x4E86;&#x6E90;&#x81EA;&#x5BF9;&#x6865;&#x8111;&#x80F6;&#x8D28;&#x7624;&#x60A3;&#x8005;&#x8FDB;&#x884C;&#x5916;&#x79D1;&#x624B;&#x672F;&#x6D3B;&#x68C0;&#x7684;&#x4EBA;&#x8111;&#x80F6;&#x8D28;&#x7624;&#x7EC6;&#x80DE;&#x7CFB;&#x3002;&#x4E3A;&#x4E86;&#x786E;&#x4FDD;&#x53EF;&#x6301;&#x7EED;&#x7684;&#x79BB;&#x4F53;&#x7E41;&#x6B96;&#xFF0C;&#x80BF;&#x7624;&#x7EC6;&#x80DE;&#x8FDB;&#x884C;&#x4E86;&#x4FEE;&#x6539;&#x4E0E;&#x7AEF;&#x7C92;&#x9176; &#xFF08;&#x7AEF;&#x7C92;&#x9176;&#x6838;&#x7CD6;&#x6838;&#x86CB;&#x767D;&#x9006;&#x8F6C;&#x5F55;&#x9176;)&#xFF0C;&#x548C;&#x8367;&#x5149;&#x7D20;&#x9176;&#x62A5;&#x9053;&#xFF0C;&#x4F7F;&#x65E0;&#x521B;&#x751F;&#x7269;&#x53D1;&#x5149;&#x6210;&#x50CF;&#x3002;HTERT &#x4FEE;&#x6539;&#x7684;&#x5355;&#x5143;&#x683C;&#x662F;&#x556E;&#x9F7F;&#x52A8;&#x7269;&#x5B9E;&#x9A8C;&#xFF0C;&#x5728;&#x81F4;&#x7624;&#x6027;&#xFF0C;&#x4EA7;&#x751F;&#x627C;&#x8981;&#x91CD;&#x8FF0;&#x6D78;&#x6DA6;&#x751F;&#x957F;&#x7684;&#x8111;&#x5E72;&#x80F6;&#x8D28;&#x7624;&#x60A3;&#x8005;&#x7684;&#x8111;&#x5E72;&#x80BF;&#x7624;&#x3002;

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Diffuse intrinsic pontine gliomas arise almost exclusively in children, and despite advances in treatment, the majority of patients die within 2Â years after initial diagnosis. Because of their infiltrative nature and anatomic location in an eloquent area of the brain, most pontine gliomas are treated without a surgical biopsy. The corresponding lack of tissue samples has resulted in a limited understanding of the underlying genetic and molecular biologic abnormalities associated with pontine gliomas, and is a substantial obstacle for the preclinical testing of targeted therapeutic agents for these tumors. We have established a human glioma cell line that originated from surgical biopsy performed on a patient with a pontine glioma. To insure sustainable in vitro propagation, tumor cells were modified with hTERT (human telomerase ribonucleoprotein reverse transcriptase), and with a luciferase reporter to enable non-invasive bioluminescence imaging. The hTERT modified cells are tumorigenic in athymic rodents, and produce brainstem tumors that recapitulate the infiltrative growth of brainstem gliomas in patients.

Characterization of a diffuse intrinsic pontine glioma cell line: implications for future investigations and treatment.

Les gliomes pontiques diffus intrins&egrave;ques surviennent presque exclusivement chez les enfants, et malgr&eacute; les progr&egrave;s r&eacute;alis&eacute;s dans le traitement, la majorit&eacute; des patients meurent dans les 2 ans apr&egrave;s le diagnostic initial. En raison de leur nature infiltrante et de l&#39;emplacement anatomique dans une zone &eacute;loquente du cerveau, plus les gliomes pontiques sont trait&eacute;s sans une biopsie chirurgicale. L&#39;absence de correspondant d&#39;&eacute;chantillons de tissus a abouti &agrave; une compr&eacute;hension limit&eacute;e de l&#39;anomalie sous-jacente g&eacute;n&eacute;tiques et mol&eacute;culaires biologiques, associ&eacute; de gliomes pontiques et est un obstacle de taille pour les essais pr&eacute;cliniques d&#39;agents th&eacute;rapeutiques cibl&eacute;s pour ces tumeurs. Nous avons cr&eacute;&eacute; une lign&eacute;e de cellules de gliome humain qui proviennent de la biopsie chirurgicale effectu&eacute;e sur un patient souffrant d&#39;un gliome pontique. Pour assurer la multiplication in vitro durable, les cellules tumorales ont &eacute;t&eacute; modifi&eacute;s avec hTERT (transcriptase inverse de la t&eacute;lom&eacute;rase humaine ribonucl&eacute;oprot&eacute;ine) et avec un journaliste de la lucif&eacute;rase pour permettre &agrave; l&#39;imagerie non invasive de bioluminescence. Les cellules de hTERT modifi&eacute; sont tumorig&egrave;nes chez les rongeurs athymique et produisent des tumeurs du tronc c&eacute;r&eacute;bral qui r&eacute;capitulent la croissance infiltrante des gliomes du tronc c&eacute;r&eacute;bral chez les patients.

Caract&eacute;risation d&#39;une lign&eacute;e de cellules d&#39;un gliome pontique diffus intrins&egrave;que : implications pour les enqu&ecirc;tes futures et de traitement.

Diffuse systeminterne Pontinische Gliome entstehen fast ausschlie&szlig;lich bei Kindern, und trotz Fortschritten in der Behandlung, die meisten Patienten sterben innerhalb von 2 Jahren nach Erstdiagnose. Wegen ihrer infiltrative Natur und anatomische Lage in einem eloquenten Bereich des Gehirns werden die meisten Pontinische Gliomen ohne eine chirurgische Biopsie behandelt. Der entsprechende Mangel an Gewebeproben f&uuml;hrte ein begrenztes Verst&auml;ndnis der zugrundeliegenden genetischen und molekularen biologischen Anomalien Pontinische Gliomen zugeordnet und ist ein wesentliches Hindernis f&uuml;r die pr&auml;klinische Pr&uuml;fung von zielgerichteten Therapeutika f&uuml;r diese Tumoren. Wir haben eine menschliche Gliom-Zelllinie etabliert, die chirurgische Biopsie durchgef&uuml;hrt, einem Patienten mit einem Pontinische Gliom stammt. Um nachhaltige in-vitro-Vermehrung zu gew&auml;hrleisten, wurden Tumorzellen mit hTERT (menschlichen Telomerase Ribonucleoprotein Reverse Transkriptase) und mit einem Luciferase Reporter nichtinvasive Biolumineszenz Bildgebung aktivieren ge&auml;ndert. Die hTERT ge&auml;ndert-Zellen sind tumorigenic in athymischen Nagetiere und Hirnstamm-Tumoren, die das infiltrative Wachstum der Hirnstamm Gliomen bei Patienten zu rekapitulieren.

Charakterisierung von einer diffusen systeminterne Pontinische Gliom-Zelllinie: Implikationen f&uuml;r k&uuml;nftige Untersuchungen und Behandlung.

Gliomi pontini intrinseci diffusi nascono quasi esclusivamente nei bambini, e nonostante i progressi nel trattamento, la maggior parte dei pazienti muore entro 2 anni dopo la diagnosi iniziale. A causa della loro natura infiltrante e posizione anatomica in un&#39;area eloquente del cervello, pi&ugrave; pontine gliomi sono trattate senza una biopsia chirurgica. La corrispondente mancanza di campioni di tessuto ha portato a una conoscenza limitata della sottostante anomalie biologiche genetiche e molecolari associate pontine gliomi e costituisce un notevole ostacolo per la sperimentazione preclinica di agenti terapeutici mirati per questi tumori. Abbiamo stabilito una linea cellulare di glioma umano che ha provenuto da biopsia chirurgica eseguita su un paziente con un glioma pontino. Per assicurare la propagazione in vitro sostenibile, le cellule tumorali sono state modificate con hTERT (ribonucleoproteina di human telomerase reverse transcriptase) e con un reporter di luciferase per abilitare imaging non invasivo bioluminescenza. Le cellule di hTERT modificati sono tumorigeno in atimico roditori e producono i tumori del tronco encefalico che riassumere la crescita infiltrativo dei gliomi del tronco encefalico in pazienti.

Caratterizzazione di una linea cellulare diffusa glioma pontino intrinseco: implicazioni per future indagini e trattamento.

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Pontine gliomas &#xD655;&#xC0B0; &#xB0B4;&#xC7A5; &#xC544;&#xC774; &#xB4E4;&#xC5D0;&#xC11C; &#xAC70;&#xC758; &#xB3C5;&#xC810;&#xC801;&#xC73C;&#xB85C; &#xBC1C;&#xC0DD; &#xD558; &#xACE0; &#xCE58;&#xB8CC;&#xC758; &#xBC1C;&#xC804;&#xC5D0;&#xB3C4; &#xBD88;&#xAD6C; &#xD558; &#xACE0; &#xD658;&#xC790;&#xC758; &#xB300;&#xB2E4;&#xC218; &#xCD08;&#xAE30; &#xC9C4;&#xB2E8; &#xD6C4; 2 &#xB144; &#xC774;&#xB0B4;&#xC5D0; &#xC8FD;&#xB294;&#xB2E4;. &#xADF8;&#xB4E4;&#xC758; infiltrative &#xC790;&#xC5F0; &#xB1CC;&#xC758; &#xC6C5; &#xBCC0; &#xC9C0;&#xC5ED;&#xC5D0;&#xC11C; &#xD574;&#xBD80;&#xD559; &#xC704;&#xCE58; &#xB54C;&#xBB38;&#xC5D0; &#xB300;&#xBD80;&#xBD84;&#xC758; pontine gliomas &#xC218;&#xC220; &#xC0DD; &#xAC80; &#xC5C6;&#xC774; &#xCC98;&#xB9AC; &#xB429;&#xB2C8;&#xB2E4;. &#xC870;&#xC9C1; &#xC0D8;&#xD50C; &#xD574;&#xB2F9; &#xBD80;&#xC871; &#xADC0;&#xCC29;&#xB418; &#xC5C8;&#xB294; &#xAE30;&#xBCF8; &#xC720;&#xC804;&#xACFC; &#xBD84;&#xC790; &#xC0DD;&#xBB3C; &#xD559;&#xC801; &#xC774;&#xC0C1;&#xC774; pontine gliomas &#xC5F0;&#xAD00;&#xC758; &#xC81C;&#xD55C; &#xB41C; &#xC774;&#xD574; &#xD558; &#xACE0; &#xC774;&#xB7EC;&#xD55C; &#xC885;&#xC591;&#xC5D0; &#xB300; &#xD55C; &#xD0C0;&#xAC9F;&#xB41C; &#xCE58;&#xB8CC;&#xC81C;&#xC758; &#xC804; &#xC784;&#xC0C1; &#xC2DC;&#xD5D8;&#xC5D0; &#xB300; &#xD55C; &#xC0C1;&#xB2F9;&#xD55C; &#xC7A5;&#xC560; &#xC774;&#xB2E4;. &#xC6B0;&#xB9AC; pontine &#xC2E0;&#xACBD;&#xC73C;&#xB85C; &#xD658;&#xC790;&#xC5D0;&#xC11C; &#xC218;&#xD589; &#xC218;&#xC220; &#xC0DD; &#xAC80;&#xC5D0;&#xC11C; &#xC778;&#xAC04;&#xC758; &#xC2E0;&#xACBD; &#xC138;&#xD3EC; &#xB77C;&#xC778;&#xC744; &#xC124;&#xB9BD; &#xD588;&#xB2E4;. &#xC9C0;&#xC18D; &#xAC00;&#xB2A5;&#xD55C; &#xC0DD;&#xCCB4; &#xC678;&#xC5D0;&#xC11C; &#xC804;&#xD30C;&#xB97C; &#xBCF4;&#xC7A5; &#xD558;&#xAE30; &#xC704;&#xD558;&#xC5EC; &#xC885;&#xC591; &#xC138;&#xD3EC; hTERT (&#xC778;&#xAC04;&#xC758; telomerase ribonucleoprotein &#xC5ED;&#xC804;&#xC0AC;)&#xC640; &#xBE44;-&#xCE68;&#xB7B5; &#xC801; &#xC0DD;&#xBB3C; &#xBC1C;&#xAD11; &#xC601;&#xC0C1; &#xC218; &#xC788;&#xB3C4;&#xB85D; &#xB8E8;&#xC2DC;&#xD398;&#xB77C;&#xC544;&#xC81C; &#xAE30;&#xC790; &#xC218;&#xC815; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC218;&#xC815; hTERT &#xC140; tumorigenic athymic &#xC124;&#xCE58;&#xB958;&#xC5D0; &#xACE0; &#xC815;&#xB9AC; brainstem gliomas &#xD658;&#xC790;&#xC5D0;&#xC11C;&#xC758; infiltrative &#xC131;&#xC7A5; brainstem &#xC885;&#xC591;&#xC744; &#xC0DD;&#xC0B0;.

&#xD655;&#xC0B0; &#xB0B4;&#xC7A5; pontine &#xC2E0;&#xACBD; &#xC138;&#xD3EC; &#xB77C;&#xC778;&#xC758; &#xD2B9;&#xC131; &#xBD84;&#xC11D;: &#xBBF8;&#xB798;&#xC758; &#xC870;&#xC0AC; &#xBC0F; &#xCE58;&#xB8CC;&#xC5D0; &#xB300; &#xD55C; &#xC758;&#xBBF8;.

Gliomas Pontinas intr&iacute;nsecos difusos ocurren casi exclusivamente en ni&ntilde;os, y a pesar de los avances en el tratamiento, la mayor&iacute;a de los pacientes muere dentro de 2 a&ntilde;os despu&eacute;s del diagn&oacute;stico inicial. Debido a su naturaleza infiltrante y localizaci&oacute;n anat&oacute;mica en un &aacute;rea elocuente del cerebro, m&aacute;s del pontine gliomas son tratados sin una biopsia quir&uacute;rgica. La correspondiente falta de muestras de tejido se ha traducido en una comprensi&oacute;n limitada de las anormalidades biol&oacute;gicas subyacentes de gen&eacute;ticas y moleculares asociados con gliomas del pontine y es un obst&aacute;culo importante para la prueba precl&iacute;nica de agentes terap&eacute;uticos dirigidos para estos tumores. Hemos establecido una l&iacute;nea de c&eacute;lulas de glioma humano que se originaron en la biopsia quir&uacute;rgica que se realiz&oacute; en un paciente con un glioma Pontino. Para asegurar la propagaci&oacute;n in vitro sostenible, las c&eacute;lulas del tumor fueron modificadas con hTERT (transcriptasa inversa de la telomerasa humana Ribonucleoprote&iacute;na) y con un reportero de luciferasa para permitir la proyecci&oacute;n de imagen no invasiva bioluminiscencia. Las c&eacute;lulas hTERT modificado son tumor&iacute;gena en roedores athymic y producen tumores de tronco encef&aacute;lico que recapitulan el crecimiento infiltrativo de gliomas de tronco cerebral en pacientes.

Caracterizaci&oacute;n de una l&iacute;nea de c&eacute;lulas de glioma Pontino intr&iacute;nseco difuso: implicaciones para futuras investigaciones y el tratamiento.

In the mature eye, three distinct tissue fates, retina, ciliary body, and iris, arrange with a strict linear organization along the central (back) to peripheral (front) axis. The establishment of this topographical relationship within the optic vesicle is not well understood. We use a targeted vital labeling strategy to test the derivation of mature eye tissues from the optic vesicle of the chick embryo. Fate mapping uncovers two distinct origins of the neural retina. Contrary to expectations, the central neural retina has a discrete origin within the posterior optic vesicle. The peripheral retina derives from the distal optic vesicle, sharing a common origin with more peripheral tissue fates. This study identifies for the first time two distinct retinal sub-domains, central and peripheral, which arise during embryogenesis. Identification of these discrete retinal compartments provides a framework for understanding functional and disease processes throughout retinal tissue.

Central and peripheral retina arise through distinct developmental paths.

Gliomas synaptically integrate into neural circuits. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

Glioblastoma remodelling of human neural circuits decreases survival.

The BBSome mediates the retrieval of ubiquitinated membrane proteins from cilia, but its physiological cargoes in photoreceptors remain largely unidentified. Here, we find that K63-linked ubiquitin (UbK63) chains accumulate in the outer segment (OS, equivalent of cilia) of   photoreceptors from the onset of OS formation. Through quantitative profiling of the UbK63-associated OS proteome, we identify the transmembrane fragment of interphotoreceptor matrix proteoglycan 2 (IMPG2) as a principal cargo of the BBSome. In   mice, ubiquitinated IMPG2 aberrantly accumulates in OSs, and disruption of IMPG2 ubiquitination impairs its retrieval and clearance. Because full-length IMPG2 traffics to the OS to deliver its extracellular domain to the matrix, our data support a model in which IMPG2 undergoes constitutive cycling between the inner and outer segments. These findings redefine the BBSome's role in photoreceptors from quality control to constitutive membrane protein turnover.

Article	Year
Optic cup morphogenesis requires pre-lens ectoderm but not lens differentiation. Developmental biology\| PubMed ID: 12871706	2003
Characterization of a diffuse intrinsic pontine glioma cell line: implications for future investigations and treatment. Journal of neuro-oncology\| PubMed ID: 22983601	2012
Central and peripheral retina arise through distinct developmental paths. PloS one\| PubMed ID: 23613848	2013
Glioblastoma remodelling of human neural circuits decreases survival. Nature\| PubMed ID: 37138086	2023
BBSome-Mediated Clearance of Ubiquitinated IMPG2 Defines a Constitutive Ciliary Retrieval Pathway in Photoreceptors. bioRxiv : the preprint server for biology\| PubMed ID: 40766594	2025

Jeanette Hyer

Biography

JoVE Journal Publications

Other Publications