Developmental origins of intrinsically photosensitive retinal ganglion cells

描述（由申请人提供）：光是各种生物体的生物学和行为的非常重要的调节器。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，它们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），视网膜上仅有的投射神经元。然而，最近的结果表明，一小部分RGC是固有光敏（ip）RGC（约2-4%的RGC），并表达色素黑视蛋白（Opn 4）。这些非典型的光感受神经节细胞主要辅助非图像形成（NIF）功能，如昼夜光诱导和瞳孔光反射（PLR）。现在有大量的证据表明，不同的形态，电生理和分子来源的ipRGC介导不同的行为。然而，引起介导这些不同行为的ipRGC的发育过程知之甚少。在发育期间发生一系列有组织的过程，其中祖细胞通过在离散时间点表达各种转录因子产生所有视网膜细胞类型。Math 5（Atoh 7）是一种碱性螺旋-环-螺旋前神经转录因子，是哺乳动物RGC决定所必需的。最近的结果表明，与传统的RGC相反，ipRGC在Math 5下调后很长时间内继续在发育中的视网膜中产生，这表明一些ipRGC的确定可能是Math 5独立的（称为非Math 5）。考虑到ipRGC也是光感受器，可能的是，至少一些非Math 5 ipRGC在发育期间依赖于负责指定经典光感受器（视杆细胞和视锥细胞）的转录因子。该提案的中心目标是表征决定ipRGC命运的发育程序。我将检验ipRGC从不同的分子谱系发展来介导不同功能的特定假设。我的初步数据表明，只有50%的ipRGC来自Math 5谱系，并且非Math 5 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Math 5是所有RGC发育所必需的，并揭示了意想不到的发现，即ipRGC可能由指定RGC（Math 5）和光感受器（Crx）的转录因子发育而来。此外，如果Crx有助于ipRGC发育，这将挑战目前认为哺乳动物RGC和光感受器从独立谱系发育的观点。

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.