小鼠是实验室中研究人类疾病进展和发育的重要的研究模型。小鼠除了在大小和外观上有不同,它们还具有和人类相似度极高的遗传背景。它们的繁殖力和快速成熟的特性使得它们成为科学研究中有效和经济的哺乳动物模型。
本视频提供了对小鼠的简单概述,包括作为生物和它们作为实验动物模型的许多优点。这个讨论将集中介绍实验室中通用的小鼠株系,包括裸鼠。它的遗传表型使得该种小鼠没有毛发并且是免疫缺陷。本视频还将介绍小鼠研究的简史,包括从它们第一次在遗传学实验中的应用一直到在免疫学和神经生物学中取得诺贝尔奖级别的发现。最后,还将介绍小鼠在不同类型研究当中的代表性案例,例如典型的行为学研究中的Morris水迷宫试验以及对哺乳动物胚胎发育的深入研究。
啮齿类动物占研究所用的实验动物的90%以上,其中的大部分是小鼠。
小鼠很容易饲养并且成本低廉,它们的遗传背景接近人类。加上它们的传代时间短和繁殖力高,使得其成为遗传调控和研究的理想的选择。
本短片将对作为模型生物的小鼠做一个概述,并且讨论它在生物学和生物医学研究中的一些应用。
通常所说的家鼠,即小鼠,属于脊椎动物家族中的哺乳动物。小鼠属于哺乳动物中最大的种群:啮齿目。这类动物的显著特点是,终生持续生长的大型啮齿,即门牙。
小鼠属于小型的哺乳动物,平均体重在出生时约为1克,在成年期到达顶峰,大约25到40克。
和其它哺乳动物相比,小鼠的生命周期也比较短。孕期大约为18到21天,新生的幼鼠无毛且视觉缺失。幼鼠在出生的前几周取食母乳,之后只需要8个星期就可以发育至性成熟。
小鼠可以适应不同的环境,所以在除了南极洲外的每个大陆都能找到它们。作为共生种群,无论我们喜欢与否,小鼠会经常贴近人类的生活。
那么为什么这些熟悉的物种会在研究中普遍用到呢?因为小鼠可以迅速繁殖大量的后代,从而快速低廉地提供科学研究所需要的动物克隆。
另外,小鼠的体积较小,可以在最小的空间里饲养。而多数其它动物则不是这样。尽管小鼠和我们之间存在着显著的物理差异,和其他的胎盘哺乳动物一样,小鼠和人类的遗传背景有着惊人的相似性。
小鼠的基因组序列已经被全部测定,这极大的方便了遗传调控,例如制备基因敲除小鼠。即用一段含有可识别标记的序列取代编码特定基因的片断,从而将小鼠的基因组修饰,敲除该基因。
利用基因敲除小鼠,我们可以评估单个基因产物的生理需要。例如在这个实验中,需要测量在缺失弗林酶时胚胎心率的变化。
现在有很多近交系小鼠的株系。因为这种小鼠个体之间的一致性可以消除由于小鼠个体之间遗传背景的多样性带来的差异,从而增加实验的可重复性。
但是怎样为您的实验选择小鼠的种系呢?答案可不是像你选择最喜欢的大衣颜色那样简单。实际上,你需要的小鼠可能根本没有大衣。这种经过遗传修饰的小鼠,即众所周知的裸鼠,它们毛发缺失,并且免疫系统功能严重降低。因此,裸鼠是将外源性组织植入整体的实验的比较好的宿主。例如在这个研究中,荧光标记的癌细胞植入后可被实时监测。
现在您已经对小鼠在科学研究中的重要性有了了解,接下来让我们来看一些利用这些模型动物,研究人员作出的令人激动的发现。
在20世纪初, William E. Castle成为第一位在实验室中使用小鼠来研究遗传学的科学家。 Castle和他的学生从 Abbie Lathrop那里得到了许多实验小鼠。后者是一个动物爱好者,在她家附近出售宠物小鼠。有意思的是,其中的一些种系,例如 C57BL/6J,直至今天仍然在实验室中被广泛应用。
20年代后期, Alexander Fleming先生在培养皿中培养细菌的时候发现了青霉素的抗生素特性,但是直到将近10年之后, Howard Florey和Ernst Chain治愈了被感染溶血性链球菌的小鼠,才确定了青霉素在药理学方面的潜在应用。
鉴于 Fleming, Florey, 和 Chain 在生物医学方面的杰出贡献,1945年,他们被授予诺贝尔奖。
几乎在抗生素被发现的同一时间, George Snell第一次描述了一个被称为主要组织相容性复合体的染色体区域。它编码可以帮助免疫细胞识别外来入侵者的受体。它们在人体内被称为人类白细胞抗原,这些受体的某些特殊变异可致自身免疫性疾病。此病是将宿主自身组织识别为异物。
此后, Rolf Zinkernagel和Peter Doherty采用了一个小鼠模型系统确定了免疫系统的T细胞对抗原的识别过程是免疫反应的开始。
在1997年, Stanley Prusiner因为在小鼠中发现朊病毒被授予诺贝尔奖 – 这是一种错误折叠的、感染性的蛋白质。见于感染了神经退行性病变—痒病的小鼠。
小鼠在 Richard Axel和Linda Buck所从事的工作中也起到重要的作用。他们首先克隆到了嗅觉受体基因大家族。这些蛋白质在嗅上皮的神经元细胞中表达,它们会与吸入的有气味的物质结合而被激活。 Buck和Axel也极大的推进了我们对这些受体产生的信号如何在神经通路中传导的理解。2004年,他们因为这些突破性的发现而被授予诺贝尔奖。
您已经看到了小鼠实验在历史上产生的里程碑式的贡献,现在让我们来看一下目前以小鼠为模型的一些研究种类。首先,小鼠被广泛用于行为学研究。
例如,小鼠是测量平衡能力方面的 一个很好的模型。小鼠还用于研究大脑如何记录和回忆,比如 Morris水迷宫就是行为学研究的典范 。在这个空间记忆的测试中,小鼠受训使用视觉标志来定位平台并从水池中逃脱。
因为我们的免疫系统功能相似,所以小鼠也是很好的用于研究感染性疾病的模型动物。例如,在这个实验中,小鼠吃掉了感染了李斯特菌的面包。然后收集小鼠不同的组织来研究这种食物携带的病原体在体内扩散的机制。
小鼠也可以用于研究病毒感染性疾病的进程。在这个研究中,通过鼻腔感染了疱疹病毒的小鼠用于模仿对病原体的生理学接触。
人类和小鼠遗传上的高度相似性不仅仅对探索人类疾病具有重要性;理解小鼠的发育过程也有益于增进对人类发育的理解。例如在这个研究中,对胚胎颚面部进行切片并培养,可以更好的观察早期牙齿的发育。
您刚观看的是JoVE对于小鼠的介绍。本短片中,我们讨论了小鼠的一般特点,例如为什么它们在实验室中得到了广泛应用,在小鼠模型中取得的里程碑式的发现,以及一些在当今的研究中使用小鼠的方法。一如既往,感谢观看JoVE的科学教育系列。
Rodents make up about 90% of all the animals used in research, the majority of which are mice.
Mice are easy and inexpensive to maintain, and their genetic similarity to humans, coupled with their short generation time and high fertility, make them ideal candidates for genetic manipulation and study.
This video provides an overview of the mouse as a model organism and discusses some of its many applications in biological and biomedical research.
The common house mouse, Mus musculus, belongs to the Mammalian class of vertebrates. Mice are found in the largest order of mammals: Rodentia, characterized by large incisors that grow continuously throughout the animal’s life.
Mice are among the smallest mammals, weighing an average of 1 g at birth and reaching their peak weight of about 25 – 40 g in adulthood.
Compared to other mammals, the mouse life cycle is also relatively short. Gestation lasts only 18 – 21 days, at which point the pups are born hairless and blind. While they feed off their mother’s milk for the first few weeks of life, the pups will develop into sexually mature adults by just 8 weeks of age.
Due to their ability to adapt to a variety of environments, mice can be found on every continent except Antarctica. As a commensal species, mice frequently live in close association with humans; whether we like it or not!
So why are these familiar creatures so popular in research?
The ability of mice to quickly produce large numbers of offspring allows the rapid and inexpensive generation of a colony of animals for scientific investigation. Additionally, the fact that mice are so small means that the colony can be housed in a minimum amount of space. The same cannot be said for most mammals.
Despite our considerable physical differences, mice and other placental mammals share a striking genetic similarity to humans. The mouse genome has been fully sequenced, which facilitates genetic manipulations such as the generation of “knockout” mice, whose genomes are modified to replace a segment encoding specific genes with selectable markers, thereby knocking out that gene.
Using knockout mice, we can assess the physiological requirement for individual gene products, as in this experiment measuring changes in embryonic heart rate caused by absence of the enzyme Furin.
Many families of inbred mouse strains exist. Because their uniformity eliminates the variables that may be introduced by genetic diversity among individual mice, the use of these strains improves experimental reproducibility.
But which strain will you choose for your experiment? The answer depends on more than your favorite coat color. In fact, you might even want a mouse with no coat at all! The genetic makeup of this little critter, known as the nude mouse, leads to missing hair, but also a severely compromised immune system. As a result, nude mice serve as better hosts for in vivo experiments where foreign tissue is introduced, as in this study monitoring the engraftment of fluorescent cancer cells.
Now that you have an understanding of just how important mice are to science, let’s talk about some exciting discoveries researchers have made using these model animals.
In the early 20th century, William E. Castle became the first scientist to use mice to study genetics in the lab. Castle and his students obtained many of their research subjects from Abbie Lathrop, a fancier who sold mice as pets from her nearby home. Interestingly, some of these strains, such as the C57BL/6J line, are still commonly used in research labs today.
In the late 1920s, Sir Alexander Fleming had discovered the antibiotic properties of penicillin using bacteria in a petri dish, but it wasn’t until almost 10 years later that Howard Florey and Ernst Chain confirmed its pharmacological potential by healing mice infected with hemolytic streptococci.
In 1945, Fleming, Florey, and Chain were recognized for their Nobel prize-winning contributions to the field of biomedicine.
Around the same time antibiotics were being discovered, George Snell first described the a chromosomal region known as the major histocompatibility complex, which encodes receptors that help immune cells detect foreign invaders. Known as human leukocyte antigens in humans, specific variants of these receptors are linked to autoimmune disorders, where host tissue is mistakenly identified as foreign.
Rolf Zinkernagel and Peter Doherty then used a mouse model system to determine that antigen recognition by the immune system’s T cells is responsible for the initiation of the immune response.
In 1997, Stanley Prusiner was awarded the Nobel prize for identifying prions — misfolded, infectious proteins — in mice infected with the neurodegenerative disease, scrapie.
Mice were also instrumental in the work performed by Richard Axel and Linda Buck, who first cloned the large family of olfactory receptor genes. These proteins, expressed by neurons in the olfactory epithelium, are activated by binding to inhaled odorants. Buck and Axel also significantly advanced our understanding of how the signals produced by these receptors are transmitted through our neural circuitry. In 2004, they were awarded the Nobel prize for their groundbreaking discoveries.
Now that you’ve seen how mouse work has produced some landmark experiments historically, let’s take a look at some of the types of research going on in mice today. To begin, mice are frequently used in behavioral research.
For example, mice make great models for measuring motor balance. They are also used to study how the brain records and recalls memories, with behavioral paradigms such as the Morris water maze. In this test of spatial memory, mice are trained to use visual cues to locate a platform and escape from a pool of water.
Because our immune systems function similarly, mice are also good systems for studying infectious disease. For example, in this experiment, mice consume bread contaminated with Listeria and then various tissues are collected to investigate the mechanism by which this food-borne pathogen spreads throughout the body.
Mice can be used to study viral disease progression as well. In this study, mice are infected intranasally with herpes virus in order to mimic physiological exposure to the pathogen.
Our high genetic similarity is not just important for investigating human disease; understanding mouse development can also improve our understanding of human development. For example, in this study, embryonic jaws are sectioned and grown in culture to better visualize early tooth development.
You just watched JoVE’s introduction to Mus musculus. In this video, we discussed general characteristics of mice, why they are so popular in the lab, landmark discoveries made in this model, as well as a few of the ways in which mice are used in research today. As always, thanks for watching JoVE Science Education!
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