MOLECULAR DEVELOPMENT OF CENTRAL RETINAL PATHWAYS

描述(改编自申请人的摘要)：愿景可以说是 我们最重要的感觉和行为在很大程度上决定了我们的行为。适当的 视觉系统的功能需要高度特定的连接 视网膜及其中枢神经系统(CNS)靶点 发育过程中精确的轴突引导的结果。我们的长期目标是 在分子水平上了解视网膜神经节细胞(RGC)轴突如何导航 在发育中的大脑中，并找到到达特定中枢神经系统位置的途径。这里, 研究将调查1)控制RGC轴突退出的轴突引导线索 视网膜进入视神经和生长锥信号分子所需 视束沿间脑外侧壁形成。在……里面 我们之前的研究发现，在缺乏轴突引导的小鼠胚胎中 视盘上的netrin-1或其在RGC轴突上的受体DCC，大多数 RGC轴突不能通过视盘生长到视神经。 最近，我们发现轴突引导线索的信号素家族中的一个成员 在视盘中也以类似于netrin-1的模式表达。在 建议的工作，我们将确定这种视盘信号素是否抑制或 促进RGC轴突生长，并使用基因靶向策略研究如何 其功能的丧失会影响视神经的发育。细胞内 体内轴突引导的信号通路在很大程度上是未知的。 GAP-43是一种细胞内生长锥蛋白，在体外通过 具有PKC、钙调蛋白和G等信号中间体的定义结构域 蛋白质及其效应器。GAP-43缺陷胚胎中的RGC轴突不能 从视交叉生长到间脑的侧壁形成 视神经束。目前尚不清楚GAP-43在体内是否通过PKC发挥作用 钙调素的激活和释放或直接影响G蛋白 发信号。我们将分析这些相互作用在光学中的确切作用 通过杂交表达工程形式的转基因动物来进行肠道发育 GAP-43缺陷小鼠。正常视束的存在 由这种杂交产生的动物将识别必要的相互作用域 GAP-43在体内发挥作用。这两组拟议的研究加在一起将 加深我们对视神经和视束形成的理解； 视觉通路的两个关键部分。这些结果还可以提供 对视神经等发育障碍的病因的洞察 并有助于促进视觉功能的恢复 受伤或疾病后的系统。

DESCRIPTION (Adapted From The Applicant's Abstract): Vision is arguably one of our most important senses and accounts for much of our behavior. The proper function of the visual system requires highly specific connections between the retina and its central nervous system (CNS) targets which come about as a result of precise axonal guidance during development. Our long term goal is to understand at a molecular level how retinal ganglion cell (RGC) axons navigate within the developing brain and find their way to specific CNS sites. Here, studies will investigate 1) axon guidance cues controlling RGC axon exit from the retina into the optic nerve and 2) growth cone signaling molecules needed for optic tract formation along the lateral wall of the diencephalon. In previous studies we found that in mouse embryos lacking the axon guidance cure netrin-1 at the optic disc, or its receptor DCC on RGC axons, the majority of RGC axons are unable to grow through the optic disc into the optic nerves. Recently, we found that a member of the semaphorin family of axon guidance cues is also expressed at the optic disc in a pattern similar to netrin-1. In the proposed work, we will determine whether this optic disc semaphorin inhibits or promotes RGC axon growth, and use gene targeting strategies to study how elimination of its function affects optic nerve development. The intracellular signaling pathways which underlie axon guidance in vivo are largely unknown. GAP-43 is an intracellular growth cone protein that in vitro interacts via defined domains with signaling intermediates such as PKC, calmodulin, and G proteins and their effectors. RGC axons in GAP-43 deficient embryos are unable to grow from the optic chiasm into the lateral wall of the diencephalon to form the optic tracts. It is not known whether GAP-43 in vivo functions through PKC activation and release of calmodulin or by directly affecting G protein signaling. We will analyze the precise role of these interactions in optic tract development by crossing transgenic animals expressing engineered forms of GAP-43 with GAP-43 deficient mice. The presence of normal optic tracts in animals resulting from such crosses will identify interaction domains necessary for GAP-43 function in vivo. Together, these two sets of proposed studies will further our understanding of the formation of the optic nerve and optic tract; two critical segments of the visual pathway. The results may also provide insight into the etiology of the developmental disorders such as optic nerve hypoplasia and assist in attempts to promote functional recovery in the visual system after injury or disease.