Molecular patterning and specification of the fovea during retinal development.

视网膜发育过程中中央凹的分子模式和规格。

• 批准号: 8595932
• 负责人: Nathan A. Mundell
• 金额: $ 5.22万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595932
• 关键词: Ablation; Age related macular degeneration; Aging; Anterior; Area; Birds; Boxing; Brain; Cell Therapy; Chickens; Color Visions; Complex; Degenerative Disorder; Development; Dorsal; Ectopic Expression; Embryo; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Homeobox Genes; Human; In Situ Hybridization; Label; Maps; Messenger RNA; Molecular; Molecular Profiling; Mus; Natural regeneration; Optic vesicle; Organism; Pathway interactions; Pattern; Pattern Formation; Photoreceptors; Phylogeny; Plasmids; Population; Primates; Reporter; Retina; Retinal; Retinal Cone; Sensory; Signal Transduction; Specific qualifier value; Spottings; Staging; Stem cells; Structure; Surface; Testing; Tissues; To specify; Transgenic Organisms; Undifferentiated; Winged Helix; Zebrafish; clinically relevant; fetal; fovea centralis; gene function; insight; macula; neural circuit; neurogenesis; novel; overexpression; prevent; progenitor; public health relevance; research study; retinal progenitor cell; retinal rods; retinotectal; transcription factor; transcriptome sequencing; visinin; visual information; zebra finch

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.

描述（由申请人提供）：脊椎动物视网膜是高度特化的感觉组织，其中复杂的神经回路起检测、解释和传递视觉信息的作用 到大脑。在许多生物体中，多能视网膜祖细胞在位置上被指定为 在最初未分化的神经视网膜片的表面上产生光感受器的不对称图案。这种模式的一个结果是产生一个中心无杆点，对应于灵长类动物的黄斑（黄斑）和鸟类的中央区域，负责高敏锐度的色觉。由于人类中央凹对退行性疾病（包括视网膜相关性黄斑变性）高度敏感，因此了解中央凹在发育过程中如何产生具有直接的临床相关性。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。虽然很少有明确的早期中央区祖细胞的标志物已被确定，在鸡胚胎中的消融实验表明，视网膜祖细胞的位置身份设置在视泡阶段，神经发生之前。几种转录因子在早期鸡视网膜的背腹（D-V）和前后（A-P）轴上不对称表达，在视网膜的区域图案中起作用，并且是正确的视网膜顶盖映射所必需的。确定这些基因在视网膜图案形成过程中的功能可以为理解中央祖细胞如何被指定形成RFZ提供起点。为了测试的假设，即中央区的祖细胞是一个分子不同的人口和他们的位置的身份是由转录因子调节不对称表达的背腹和前后域的视网膜，我提出了以下目标：具体目标1：确定基因特异性表达的小鸡中央区测试的假设，视网膜祖细胞，引起的RZ分子不同。具体目标2：确定A-P，D-V和RFZ基因表达模式是否在整个胚胎发育中共享。具体目标3：确定模式化转录因子之间的相互抑制作用是否足以建立RFZ。这里提出的实验利用遗传和卵内操作来确定RFZ祖细胞的分子身份，并确定区域转录因子在中央区域建立过程中的功能。这些目标的成功完成将为感光模式形成机制带来新的见解，这是目前几乎完全未知的。此外，对黄斑区的了解可以提供对人类衰老期间该结构的高度脆弱性的见解。