Molecular Networks Controlling Subtype Specification of Color Photoreceptors

描述（由申请人提供）：神经元规格的精确控制是形成高度复杂神经系统的先决条件。此外，神经系统损伤和变性涉及特定神经元群的损失，因此，理解神经元亚型特化的潜在机制与人类健康相关。我的实验室和其他人已经确定了许多关键的命运决定因素，涉及指定不同的感光神经元亚型，使用遗传上顺从的果蝇眼睛作为模型系统。最近，我们发现四个保守的转录因子-[Otd（脊椎动物中的OTX/CRX），Tj（MAF/NRL），无意义（GFI1）和Pph13（ARX）]-在蓝色和绿色光感受器（PR）之间的二元命运选择中起着至关重要的作用。此外，我们证明，这些PR命运决定因素差异调节表达和/或活性的两个关键组成部分的河马肿瘤抑制途径-WTS和YKI-控制细胞类型特异性基因表达的蓝色与绿色PR。虽然Hippo通路以其在生长控制中的作用而闻名，但我们的研究揭示了Hippo通路如何控制有丝分裂后细胞中细胞命运的新机制。在这里，我们提出的实验，以扩大我们的知识，河马途径如何控制细胞命运的规范，测试的核心假设，PR命运决定因素和河马途径介质之间的串扰是至关重要的蓝色和绿色PR之间的精确的二进制细胞命运的选择。利用遗传学、生物化学和分子生物学的方法，我们建议定义PR命运决定子和Hippo通路之间的关键串扰节点，并阐明其潜在的分子机制。这些节点包括a）蓝色PR与绿色PR中Hippo途径效应物Sd的差异作用（目标1）; b）蓝色和绿色PR中Hippo途径调节物-melt和wts的调节（目标2）;和c）Hippo和Smad依赖性信号传导之间的串扰，以确保二元命运决定（目标3）。这项研究的结果将作为一个重要的指导未来的研究中的作用，海马通路在PR规范在其他生物体，神经元的规范一般。

DESCRIPTION (provided by applicant): Precise control of neuronal specification is a prerequisite for the formation of a highly complex nervous system. Moreover, nervous system injury and degeneration involves a loss of specific groups of neurons, and therefore, understanding the mechanisms underlying neuronal subtype specification has relevance to human heath. My lab and others have identified numerous key fate determinants involved in specifying distinct photoreceptor neuron subtypes, using the genetically amenable Drosophila eye as a model system. Recently, we showed that four conserved transcription factors - [Otd (OTX/CRX in vertebrates), Tj (MAF/NRL), Senseless (GFI1), and Pph13 (ARX)] - play crucial roles in binary fate choices between blue and green photoreceptors (PRs). Moreover, we demonstrated that these PR fate determinants differentially regulate the expression and/or activity of two key components of the Hippo tumor suppressor pathway - Wts and Yki - to control cell type-specific gene expression in blue vs green PRs. While the Hippo pathway is well known for its role in growth control, our study revealed novel mechanistic insights into how the Hippo pathway controls cell fate specification in postmitotic cells. Here, we propose experiments to expand our knowledge on how the Hippo pathway controls cell fate specification, testing the central hypothesis that cross-talk between PR fate determinants and Hippo pathway mediators is critical for precise binary cell fate choices between blue and green PRs. Using genetic, biochemical and molecular approaches, we propose to define key crosstalk nodes between the PR fate determinants and the Hippo pathway and elucidate their underlying molecular mechanisms. These nodes include a) differential actions of the Hippo pathway effector Sd in blue vs green PRs (Aim 1); b) regulation of the Hippo pathway regulators - melt and wts - in blue and green PRs (Aim 2); and c) crosstalk between Hippo and Smad-dependent signaling to ensure a binary fate decision (Aim 3). Outcomes of this study will serve as an important guide for future studies on the role of the Hippo pathway in PR specification in other organisms, and for neuronal specification in general.