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: 8013370
• 负责人: Carol A. Mason
• 金额: $ 20.09万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013370
• 关键词: Address; Animals; Area; Axon; Binocular Vision; Brain; Candidate Disease Gene; Cell Adhesion Molecules; Code; Contralateral; Defect; Depth Perception; Development; Dorsal; Ectopic Expression; Electroporation; Ephrin Receptor EphB1; Eye; Funding; Gene Delivery; Gene Expression; Genes; Genetic Models; Grant; In Vitro; Ipsilateral; Lateral Geniculate Body; Lead; Ligands; Mediating; Methods; Molecular; Mus; Neuraxis; Neuroglia; Normal Statistical Distribution; Nose; Optic Chiasm; Pathway interactions; Pattern; Peripheral; Phenotype; Pigments; Principal Investigator; Radial; Research; Retina; Retinal; Retinal Ganglion Cells; Role; Route; Semaphorins; Shapes; Side; Specific qualifier value; Staging; System; To specify; Transcriptional Regulation; Up-Regulation; Visual; Visual Acuity; Work; albino mouse; axon guidance; base; gene function; in utero; in vitro Assay; in vivo; innovation; meetings; mutant; programs; public health relevance; receptor; receptor expression; response; retinal axon; transcription factor

DESCRIPTION (provided by applicant): This grant is aimed at understanding how transcription factor codes 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 ipsilateral projection through the mouse optic chiasm: The transcription factor Zic2 and the guidance receptor EphB1 are expressed in ventrotemporal (VT) retinal ganglion cells (RGCs), which give rise to the ipsilateral projection. EphrinB2 is expressed on radial glia at the optic chiasm midline, and the repulsive EphB1-ephrinB2 interaction produces the ipsilateral projection. Zic2 and EphB1 expression correlate with the degree of binocularity across species and in genetic models with a reduced ipsilateral projection, such as the albino. In the last funding period, we determined that EphB1 expression is downregulated in Zic2 mutants and upregulated after ectopic expression of Zic2; thus, Zic2 controls EphB1 expression. Further, Zic2 is necessary and sufficient to drive an ipsilateral projection in vivo and in vitro. We also found that Foxd1 is expressed in the VT quadrant and is required for Zic2 and EphB1 expression, placing Foxd1 upstream of this transcriptional program for the ipsilateral projection. In other studies, we found that the Ig-CAM NrCAM and the Semaphorin receptor PlexinA1 are expressed by RGCs in non-VT and late-forming VT retina, both regions giving rise to the contralateral projection. NrCAM appears to modulate an inhibitory response by RGCs to semaphorins, as found for midline crossing in other systems. In Aim 1, we will continue a focus on Zic2 and identify additional genes regulated by Zic2. The transcription factor Islet2 has an identical expression pattern to NrCAM and PlexinA1, but its role is restricted to the late-born crossed projection from VT, similar to NrCAM. Therefore, we will focus on the late VT retina and determine whether Islet2 controls NrCAM and/or PlexinA1 expression to encode the contralateral retinal projection from this region. We will also determine if Islet2 interacts functionally with Zic2. In Aim 2, we will search for additional genes that may specify the retinal sectors giving rise to the crossed and uncrossed projection, and investigate whether Foxg1 (the nasal counterpart to Foxd1) is upstream of the contralateral program. In Aim 3, we will apply information gained from Aims 1 and 2 to understand how the the albino retina is (mis)specified to produce a diminished ipsilateral projection. Aim 4 will examine whether the genes important for RGC and retinal specification implement midline guidance and/or targeting of eye- specific zones in the dorsal lateral geniculate nucleus (dLGN). These studies use innovative methods for gene delivery (in utero and ex vivo electroporation), in vitro assays, and circuit tracing to define the molecular control of the formation of binocular visual projections. PUBLIC HEALTH RELEVANCE: This research aims to understand how retinal ganglion cells grow out from each eye, meet at the X-shaped optic chiasm, then diverge toward targets on both sides of the brain. Proper binocular vision is dependent on a normal distribution of retinal axons crossing at the optic chiasm, and if altered, reduced visual acuity and depth perception ensue. This work investigates the genes that pattern the retina into sectors giving rise to crossed and uncrossed projections and that drive expression of guidance receptors to enable retinal axons to take the appropriate route.

描述（由申请人提供）：该基金旨在了解转录因子编码如何使视网膜图案化并控制指导受体表达，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同侧投影通过小鼠视交叉：转录因子Zic 2和指导受体EphB 1在腹颞（VT）视网膜神经节细胞（RGC），这引起同侧投影。EphrinB 2在视交叉中线处的放射状胶质细胞上表达，并且排斥性EphB 1-EphrinB 2相互作用产生同侧投射。Zic 2和EphB 1表达与跨物种的双眼性程度相关，并且在具有减少的同侧投影的遗传模型中，例如白化病。在上一个资助期，我们确定EphB 1的表达在Zic 2突变体中下调，在Zic 2异位表达后上调;因此，Zic 2控制EphB 1的表达。此外，Zic 2是必要的和足够的，以驱动体内和体外的同侧投影。我们还发现，Foxd 1在VT象限中表达，并且是Zic 2和EphB 1表达所必需的，将Foxd 1置于同侧投射的转录程序的上游。在其他研究中，我们发现Ig-CAM NrCAM和脑信号蛋白受体丛蛋白A1在非VT和晚期形成的VT视网膜中由RGCs表达，这两个区域都引起对侧投射。NrCAM似乎调节RGCs对信号蛋白的抑制反应，如在其他系统中发现的中线交叉。在目标1中，我们将继续关注Zic 2，并确定由Zic 2调控的其他基因。转录因子Islet 2与NrCAM和丛蛋白A1具有相同的表达模式，但其作用限于VT的晚生交叉投射，与NrCAM相似。因此，我们将重点关注晚期VT视网膜，并确定Islet 2是否控制NrCAM和/或丛蛋白A1表达，以编码来自该区域的对侧视网膜投射。我们还将确定Islet 2是否与Zic 2在功能上相互作用。在目标2中，我们将寻找可能指定引起交叉和非交叉投射的视网膜部分的其他基因，并调查Foxg 1（Foxd 1的鼻对应物）是否位于对侧程序的上游。在目标3中，我们将应用从目标1和2获得的信息来理解白化病视网膜是如何（错误）指定以产生减少的同侧投影的。目的4将检查对RGC和视网膜特化重要的基因是否实现中线引导和/或靶向背外侧膝状体核（dLGN）中的眼睛特异性区。这些研究使用创新的方法进行基因传递（在子宫内和离体电穿孔），体外测定和电路跟踪，以确定形成双眼视觉投射的分子控制。公共卫生关系：这项研究旨在了解视网膜神经节细胞如何从每只眼睛中生长出来，在X形视交叉处相遇，然后向大脑两侧的目标发散。正常的双眼视觉取决于视网膜轴突在视交叉处的正常分布，如果改变，则会导致视力和深度知觉的降低。这项工作调查的基因，图案的视网膜到部门引起交叉和非交叉的投影，并驱动表达的指导受体，使视网膜轴突采取适当的路线。