The Role of Zic Genes in Patterning the Binocular Projection

Zic 基因在双眼投影模式中的作用

• 批准号: 9130223
• 负责人: Carol A. Mason
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130223
• 关键词: Address; Applications Grants; Area; Axon; Binding; Binocular Vision; Brain; Cell Differentiation process; Cells; Complex; Contralateral; Depth Perception; Dorsal; Ephrin Receptor EphB1; Eye; Foxes; Gene Expression; Gene Expression Profiling; Genes; Genetic; Goals; Growth; Indigenous; Injury; Ipsilateral; Knockout Mice; Lateral Geniculate Body; Mediating; Mus; Natural regeneration; Neuroglia; Neurons; Normal Statistical Distribution; Nose; Optic Chiasm; Pathway interactions; Pattern; Play; Promoter Regions; Radial; Regulation; Repression; Research; Retina; Retinal; Retinal Ganglion Cells; Role; Route; Semaphorins; Shapes; Side; Specific qualifier value; Stem cells; Testing; Transcriptional Regulation; Visual; Visual Acuity; Winged Helix; Work; axon guidance; axon regeneration; differential expression; gain of function; insight; meetings; mouse model; nerve supply; novel; plexin; programs; receptor; receptor expression; research study; retinal axon; stem cell therapy; success; transcription factor; transcription factor USF

DESCRIPTION (provided by applicant): This grant application aims to understand the gene pathways that pattern the retina and control guidance receptor expression to establish the crossed and uncrossed visual projections. Our previous work defined such a program for the uncrossed or ipsilateral projection: the guidance receptor EphB1 is expressed in ventrotemporal (VT) retinal ganglion cells (RGCs), and repulsive interactions between EphB1-expressing VT RGCs and EphrinB2-expressing radial glia at the optic chiasm midline establish the ipsilateral projection. The transcription factor Zic2 controls EphB1 expression, is necessary and sufficient for inducing an ipsilateral projection, and regulates factors important for activity-dependent target innervation. We have recently identified a contralateral RGC midline guidance program: the Ig-CAM Nr-CAM and the semaphorin receptor Plexin-A1, expressed by contralateral RGCs and optic chiasm cells, form a complex with midline Sema6D to convert inhibition into growth of contralateral RGC axons. However, little is known about the transcriptional control of the contralateral RGC projection. The proposed studies seek to uncover transcriptional networks controlling ipsilateral and contralateral RGC identity and retinal patterning. Aim 1 will analyze transcriptional pathways of the contralateral projection. We have discovered that the SoxC group of transcription factors (Sox4, 11 and 12) is expressed in crossed but not uncrossed RGCs and binds to the promoter regions of Plexin-A1 and Nr-CAM. Using a mouse model conditionally removing all three SoxCs, we will determine whether SoxCs regulate the contralateral projection through directing contralateral guidance molecule expression. We will also determine whether Zic2 represses contralateral genes to maintain uncrossed RGC identity. In Aim 2, we will further investigate how crossed and uncrossed projections are specified by focusing on transcription factors upstream of those studied in Aim 1, namely, Foxg1 and Foxd1. Foxd1 is expressed in the VT retina and is required for Zic2 and EphB1 expression, thus placing it upstream of the transcriptional program for the ipsilateral projection. As Foxg1 is expressed in the areas giving rise to contralaterally projecting RGCs, we will investigate whether Foxg1 controls the contralateral projection through regulation of contralateral gene expression, using a novel conditional Foxg1 mouse. In Aim 3, we build on our recent success in gene expression profiling to identify genes that are differentially expressed in ipsilateral versus contralateral RGCs. We will characterize their expression patterns and roles in directing the formation of the binocular circuit. Together, these studies will illuminate how the ipsilateral and contralateral retinal sectors are specified - information that is essential for implementing regeneration of indigenous RGCs or their stem cell replacements.

描述（由申请人提供）：该资助申请旨在了解视网膜模式和控制指导受体表达的基因途径，以建立交叉和非交叉视觉投射。我们以前的工作定义了这样一个程序的非交叉或同侧的投影：指导受体EphB 1的腹颞（VT）视网膜神经节细胞（RGCs）的表达，和排斥之间的相互作用EphB 1表达VT RGCs和EphrinB 2表达放射状胶质细胞在视交叉中线建立同侧的投影。转录因子Zic 2控制EphB 1的表达，是诱导同侧投射所必需的和充分的，并调节对活动依赖性靶神经支配重要的因子。我们最近已经确定了对侧RGC中线指导计划：Ig-CAM Nr-CAM和脑信号蛋白受体丛蛋白A1，表达对侧RGC和视交叉细胞，形成一个复合物与中线Sema 6D转换成对侧RGC轴突的生长抑制。然而，很少有人知道对侧RGC投射的转录控制。拟议的研究旨在揭示控制同侧和对侧RGC身份和视网膜图案的转录网络。目的1分析对侧投射的转录途径。我们已经发现，SoxC组的转录因子（Sox 4，11和12）在交叉的但不是非交叉的RGC中表达，并结合到丛蛋白-A1和Nr-CAM的启动子区。使用小鼠模型有条件地去除所有三个SoxCs，我们将确定SoxCs是否通过指导对侧引导分子表达来调节对侧投射。我们还将确定Zic 2是否抑制对侧基因以维持未交叉的RGC身份。在目标2中，我们将进一步研究交叉和非交叉投影是如何通过关注目标1中研究的转录因子上游，即Foxg 1和Foxd 1来指定的。Foxd 1在VT视网膜中表达，并且是Zic 2和EphB 1表达所需的，因此将其置于同侧投射的转录程序的上游。由于Foxg 1表达于 区域产生对侧投射的RGC，我们将研究Foxg 1是否通过调节对侧基因表达来控制对侧投射，使用一种新的条件Foxg 1小鼠。在目标3中，我们建立在我们最近成功的基因表达谱，以确定基因的差异表达在同侧与对侧RGC。我们将描述它们的表达模式和在指导双眼回路形成中的作用。总之，这些研究将阐明同侧和对侧视网膜部门是如何指定的-信息是必不可少的实施再生的土著RGC或其干细胞替代。