MOLECULAR DEVELOPMENT OF CENTRAL RETINAL PATHWAYS

描述（改编自申请人摘要）：视觉可以说是其中之一 我们最重要的感官和解释我们的大部分行为。适当的 视觉系统的功能需要高度特定的连接之间的 视网膜及其中枢神经系统（CNS）靶点， 在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，找到它们到达特定中枢神经系统部位的途径。在这里， 研究将调查1）轴突指导线索控制RGC轴突退出 视网膜进入视神经和2）生长锥信号分子需要 用于沿着间脑侧壁形成视束。在 我们先前的研究发现，在缺乏轴突引导治疗的小鼠胚胎中， netrin-1在视盘，或其受体DCC在RGC轴突，大多数的 RGC轴突不能通过视盘生长到视神经中。 最近，我们发现轴突导向信号的信号蛋白家族的一个成员， 也以类似于netrin-1的模式在视盘表达。在 建议的工作，我们将确定是否这种视盘信号蛋白抑制或 促进RGC轴突生长，并使用基因靶向策略来研究如何 其功能的消除影响视神经的发育。细胞内 在体内作为轴突导向基础的信号传导途径在很大程度上是未知的。 GAP-43是一种细胞内生长锥蛋白，其在体外通过以下途径相互作用： 具有信号传导中间体如PKC、钙调蛋白和G 蛋白质及其效应物。GAP-43缺陷胚胎中的RGC轴突不能 从视交叉长到间脑的外侧壁 视神经束GAP-43在体内是否通过PKC发挥作用尚不清楚 激活和释放钙调素或直接影响G蛋白 信号我们将分析这些相互作用在光学中的确切作用 通过杂交表达工程化形式的转基因动物来开发 GAP-43与GAP-43缺陷型小鼠。正常视神经束的存在， 由这种杂交产生的动物将鉴定出必需的相互作用域， GAP-43在体内的功能。这两套拟议的研究将共同 进一步了解视神经和视束的形成; 视觉通路的两个关键部分。研究结果还可能提供 深入了解视神经等发育障碍的病因 发育不全，并协助试图促进视觉功能恢复 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.