Developmental origins of intrinsically photosensitive retinal ganglion cells

描述(由申请人提供)：光是生物学和各种生物体行为的一个极其重要的调节器。几十年来，视杆细胞和视锥细胞被认为是视网膜中唯一的感光细胞，将光信号传递给大脑进行视觉处理 通过视网膜神经节细胞(RGC)，这是视网膜唯一的投射神经元。然而，最近的研究表明，少数视网膜节细胞是固有的光敏性(IP)视网膜节细胞(约占视网膜节细胞的2-4%)，并且表达光色素黑素(Opn4)。这些非典型的感光神经节细胞主要具有非成像(NIF)功能，如昼夜节律的光捕获和瞳孔光反射(PLR)。现在有大量证据表明，不同形态、电生理和分子来源的ipRGC调节不同的行为。然而，调节这些不同行为的ipRGC的发育过程却鲜为人知。在发育过程中会发生一系列有组织的过程，在这些过程中，祖细胞通过在离散的时间点表达各种转录因子来产生所有类型的视网膜细胞。Math5(Atoh7)是哺乳动物RGC测定所必需的一种基本的螺旋-环-螺旋原神经转录因子。最近的结果表明，与传统的RGC相反，在Math5下调后很长一段时间内，ipRGC仍在发育中的视网膜中产生，这表明一些ipRGC的确定可能不依赖于Math5(称为非Math5)。鉴于ipRGC也是光感受器，可能至少有一些非Math5的ipRGC依赖于转录因子，这些转录因子在发育过程中负责指定经典的光感受器，即视杆和视锥。这项提案的中心目标是描述决定ipRGC命运的发展计划的特征。我将测试特定的假设，即ipRGC从不同的分子谱系发育而来，调节不同的功能。我的初步数据表明，只有50%的ipRGC来自Math5谱系，而非Math5的ipRGC表达转录因子CRX，这是一种对经典光感受器发育至关重要的转录因子。这些初步数据挑战了长期以来的教条，即Math5对于所有RGC的发育都是必要的，并揭示了意外的发现，即ipRGC可能是由同时指定RGC(Math5)和光受体(CRX)的转录因子发育而来的。此外，如果CRX有助于ipRGC的发育，这将挑战目前的观点，即哺乳动物的RGC和光感受器是从独立的谱系发展而来的。

DESCRIPTION (provided by applicant): Light is a profoundly important regulator of biology and behavior in a variety of organisms. For decades, rods and cones were thought to be the only photosensitive cells in the retina, conveying light signals to the brain for visual processing via retinal ganglion cells (RGCs), the only projection neurons from the retina. However, recent results indicate that a small population of RGCs are intrinsically photosensitive (ip)RGCs (~2-4% of RGCs) and express the photopigment melanopsin (Opn4). These atypical photoreceptive ganglion cells subserve primarily non-image forming (NIF) functions such as circadian photoentrainment and the pupillary light reflex (PLR). There is now substantial evidence that ipRGCs of diverse morphological, electrophysiological and molecular origins mediate distinct behaviors. However, the developmental processes giving rise to the ipRGCs that mediate these distinct behaviors are poorly understood. A series of organized processes occur during development in which progenitor cells generate all retinal cell types through the expression of various transcription factors at discrete timepoints. Math5 (Atoh7) is a basic helix-loop-helix proneural transcription factor that is necessary for mammalian RGC determination. Recent results indicate that, in contrast to conventional RGCs, ipRGCs continue to be generated in the developing retina long after Math5 is downregulated, indicating that determination of some ipRGCs may be Math5 independent (referred to as non-Math5). Given that ipRGCs are also photoreceptors, it is possible that at least some of the non-Math5 ipRGCs rely on transcription factors responsible for specifying the classical photoreceptors, rods and cones, during development. The central goal of this proposal is to characterize the developmental programs that determine ipRGC fate. I will test the specific hypothesis that ipRGCs develop from distinct molecular lineages to mediate distinct functions. My preliminary data indicate that only 50% of ipRGCs arise from the Math5 lineage and that non- Math5 ipRGCs express the transcription factor Crx, a transcription factor critical for development of the classical photoreceptors. These preliminary data challenge the long-held dogma that Math5 is necessary for the development of all RGCs and reveal the unexpected finding that ipRGCs may develop from transcription factors specifying both RGCs (Math5) and photoreceptors (Crx). In addition, if Crx contributes to ipRGC development, this will challenge the current belief that mammalian RGCs and photoreceptors develop from independent lineages.