The In Vivo Function of Id2 in Retinal Proliferation and Differentiation

描述（由申请人提供）：神经系统的构建是一系列完整的发育步骤，从分离一小群注定成为神经祖细胞的胚胎细胞开始。这些神经祖细胞然后保持增殖和未分化，直到它们已经成为不同的神经细胞的命运。在大多数神经组织中，在脊椎动物视网膜内，细胞用于控制这些过程的细胞和分子策略仍然知之甚少。更糟糕的是，大多数形式的癌症表现出对这些事件的明显失调控制，许多人类疾病的本质与这些过程中的扰动有关。因此，这个建议的总体目标是提高我们的理解的细胞内机制，神经母细胞增殖，谱系承诺和分化的发展中的脊椎动物视网膜。这将通过利用斑马鱼视网膜来理解内在因子Id2（分化抑制剂）在视网膜发育中的作用来实现。该提案的具体目标是1。为了确定Id 2在斑马鱼视网膜发生过程中的功能，2.确定Id2在发育中的斑马鱼视网膜中功能的分子机制，以及3.确定Id2是否受Sonic Hedgehog Pathway（Shh）调节。这些目标将使用Id2功能丧失和功能获得策略在体内实现，以定义Id2在斑马鱼视网膜发生期间的功能作用，并且Shh功能丧失和功能获得方法也将用于评估Id2在发育中的脊椎动物视网膜中是否受Shh调节。本实验将阐明内源性因子Id2如何调节脊椎动物眼的生长和分化，以及Shh信号通路的促有丝分裂特性如何控制其功能。由于许多人类神经系统，发育和癌症疾病的形成与细胞分裂，细胞特化和细胞存活等早期发育过程中的破坏有关，本研究的目的是提高我们对这些过程通常如何在细胞内分子水平上发生的理解，以及它们如何在发育时间内受到控制。具体来说，这项研究将研究这些事件如何在发育中的视网膜中发生，从而增加我们对视网膜如何形成的知识，并为癌症早期可能被破坏的事件提供线索，如视网膜母细胞瘤，以及影响视网膜的神经退行性疾病。

DESCRIPTION (provided by applicant): The construction of the nervous system is an integrated series of developmental steps, commencing with the segregation of a small group of embryonic cells fated to become neural progenitors. These neural progenitors then remain proliferative and undifferentiated until they have become committed to distinct neural cell fate. As in most neural tissue, within the vertebrate retina, the cell and molecular strategies that cells use to control these processes remain poorly understood. Even worse, most forms of cancer exhibit distinctly misregulated control over these events, and the nature underlying many human diseases are tied to perturbations in these processes. Therefore, the overarching goal of this proposal is to enhance our understanding of the intracellular mechanisms governing neuroblast proliferation, lineage commitment and differentiation within the developing vertebrate retina. This will be accomplished by utilizing the zebrafish retina to understand the role of the intrinsic factor Id2 (Inhiibitor of Differentiation) in retinal development. The specific Aims of this proposal are 1. To determine the function of Id2 during zebrafish retinogenesis, 2. To determine the molecular mechanisms underlying Id2 function in the developing zebrafish retina, and 3. To determine if Id2 is regulated by the Sonic Hedgehog Pathway (Shh). These Aims will be accomplished using Id2 loss and gain-of-function strategies in vivo in order to define the functional role of Id2 during zebrafish retinogenesis, and Shh loss and gain-of-function methods will also be used to assess if Id2 is regulated by Shh in the developing vertebrate retina. The experiments in this proposal will shed light on how the intrinsic factor Id2 regulates growth and differentiation of the vertebrate eye, and how it's function may be controlled by mitogenic properties of the Shh signaling pathway. As the formation of many human neurological, developmental and cancerous diseases are linked to disruptions in such early developmental processes as cell division, cell specialization and cell survival, the purpose of this study is to enhance our understanding of how these processes normally occur at the molecular level within the cell, and how they are controlled over developmental time. Specifically, this study will examine how these events occur in the developing retina, thereby increasing our knowledge of how the retina forms, and providing clues to the events that may be disrupted in the early stages of cancer, such as retinoblastoma, as well as neurodegenerative diseases affecting the retina.