Molecular patterning and specification of the fovea during retinal development.

描述(申请人提供)：脊椎动物视网膜是一种高度专业化的感觉组织，其中复杂的神经回路起到检测、解释和传递视觉信息的作用。 对大脑的影响。在许多生物中，多能视网膜祖细胞的位置被指定为 在最初未分化的神经视网膜膜表面产生不对称的光感受器图案。这种模式的一个结果是产生一个中央无杆斑点，对应于灵长类动物的中心凹(斑点)和鸟类的中央区域，这是负责高敏锐度色觉的区域。因为人的黄斑中心凹对退行性疾病非常敏感，包括老年性黄斑变性，所以了解黄斑中心凹在发育过程中是如何产生的具有直接的临床意义。然而，指导光感受器区域分布和产生无杆区(RFZ)的分子机制尚不清楚。虽然早期中心区前体细胞的明确标志物很少，但在鸡胚胎中的消融实验表明，视网膜前体细胞的位置标识设定在视泡阶段，在神经发生之前。一些转录因子在雏鸡早期视网膜的背腹(D-V)和前后(A-P)轴上不对称地表达，在视网膜的区域模式中发挥作用，是正确的视网膜顶盖定位所必需的。确定这些基因在视网膜形成过程中的功能可以为理解中央祖细胞是如何被指定形成RFZ提供一个起点。为了验证中心区祖细胞是一个分子上不同的群体以及它们的位置特性受视网膜背侧-腹区和前后区不对称表达的转录因子调控的假设，我提出了以下目标：特定目的1：寻找在鸡中央区特异表达的基因，以检验导致RZ的视网膜祖细胞在分子上是不同的假设。具体目标2：确定A-P、D-V和RFZ基因的表达模式是否在系统发育过程中是相同的。具体目标3：确定模式转录因子之间的相互抑制相互作用是否足以建立RFZ。这里提出的实验利用遗传和在卵中的操作来确定RFZ前体的分子身份，并在中央区域的建立过程中识别区域转录因子的功能。这些目标的成功实现将为目前几乎完全未知的光感受器模式形成机制带来新的见解。此外，对黄斑区的了解可能会为人类在衰老过程中这种结构的高度脆弱性提供洞察力。

DESCRIPTION (provided by applicant): The vertebrate retina is a highly specialized sensory tissue in which complex neural circuits function to detect, interpret, and relay visual information to the brain. In many organisms, multipotent retinal progenitor cells are positionally specified to generate asymmetric patterns of photoreceptors across the surface of the initially undifferentiated neuroretinal sheet. One consequence of this patterning is the generation of a central rod-free spot that corresponds to the fovea (macula) in primates, and the area centralis in birds, which are responsible for high acuity color vision. Because the human fovea is highly susceptible to degenerative diseases, including Age-Related Macular Degeneration, there is direct clinical relevance to understanding how the fovea arises during development. However, molecular mechanisms that direct regional distribution of photoreceptors and generate the rod-free zone (RFZ) are unknown. Although few definitive markers of early area centralis progenitors have been identified, ablation experiments in the chicken embryo suggest that positional identities of retinal progenitors are set at the optic vesicle stage, prior to neurogenesis. Several transcription factors expressed asymmetrically across the dorsal-ventral (D-V) and anterior-posterior (A-P) axes of the early chick retina function in regional patterning o the retina and are required for proper retinotectal mapping. Determining the function of these genes during retinal patterning can provide a starting point for understanding how central progenitors are designated to form the RFZ. In order to test the hypotheses that area centalis progenitors are a molecularly distinct population and their positional identity is regulated by transcription factors asymmetrically expressed in dorsal-ventral and anterior-posterior domains of the retina I propose the following aims: Specific Aim 1: Identify genes specifically expressed in the chick area centralis to test the hypothesis that retinal progenitors that give rise to the RZ are molecularly distinct. Specific Aim 2: Determine if A-P, D-V and RFZ gene expression patterns are shared across phylogeny. Specific Aim 3: Determine if reciprocal inhibitory interactions between patterned transcription factors are sufficient to establish the RFZ. Experiments proposed here take advantage of genetic and in ovo manipulations to determine the molecular identity of RFZ progenitors and identify the function of regional transcription factors during establishment of the area centralis. The successful completion of these aims will bring novel insights to mechanisms of photoreceptor pattern formation, which are currently almost completely unknown. Further, an understanding of the macular area may provide insights into the high degree of vulnerability of this structure during aging in humans.