Investigating Novel Transcriptional Mechanisms for Visual Neural Circuit Development and Function using Zebrafish

项目003（486）：研究视觉神经回路发展的新转录机制， 使用Zebrafish、Bergeron、PL的函数 项目总结/摘要 与神经发育障碍相关的神经解剖学和行为变化，如眼动追踪 精神分裂症中的功能障碍，是由未知的遗传机制引起的。识别这些关键基因 视觉系统中的感觉运动反应网络是开发有针对性的早期 针对这些疾病的症状的诊断和预防策略， 为受其折磨的人导航我的长期目标是描述致病的遗传机制， 神经发育障碍相关的表型使用斑马鱼作为模型系统。这种强大的基因 模型提供了一个独特的机会，作为一个容易接近的脊椎动物与相对“简单”的神经 系统，快速的神经发育，许多人类疾病相关基因的直系同源物，以及定义和易于处理的 对视觉刺激的行为反应我们可以开始研究特定类别的神经元， 分子身份和功能，从他们出生的那一刻，通过在胚胎中迅速成年 与其他脊椎动物模型相比的时间。我以前的工作和其他人的工作首次揭示了 介导小鼠感觉处理和反射控制的关键中间神经元的分子身份， 斑马鱼听觉系统这些神经元表达转录因子基因组筛选同源框1（Gsx 1）， 我试图确定Gsx 1在感觉处理的神经回路的发展中所起的作用 穿过CNS。在检查靶向的gsx 1斑马鱼突变体后，我们发现神经元的严重缺陷， 分化和轴突的指导发展中的视觉系统。尽管有记载表明， 在小鼠和斑马鱼中开发视觉系统，迄今为止还没有研究来检查 Gsx 1在视觉神经回路的发育和功能中的作用。鉴于转录的重要性， 感觉系统中神经回路发育的机制以及针对感觉系统中关键参与者的拟议能力， 这些大型基因网络来治疗疾病，我们试图填补这一知识空白。本提案的目标1将 确定gsx 1突变对先天视觉介导行为和细胞命运决定的影响 在斑马鱼的前顶盖和眼睛里。目标2中描述的实验将确定细胞机制 Gsx 1通过它调节连接眼睛和大脑的顶盖前区轴突的分支。我们将 能够执行这些实验并分析和验证将生成的大量数据 在视觉功能和形态核心以及西弗吉尼亚大学基因组学核心设施的专家指导下， 和生物信息学核心设施。这项研究将提供深入了解复杂的遗传病因， 神经发育障碍，其中患者在感觉处理中具有共病缺陷。另外我们 研究将提供丰富的数据，这些数据可用于支持未来的研究项目，这些研究项目将与 随着视觉功能的发展。

Project 003 (486): Investigating Novel Transcriptional Mechanisms for Visual Neural Circuit Development and Function using Zebrafish, Bergeron, PL PROJECT SUMMARY / ABSTRACT Neuroanatomical and behavioral changes associated with neurodevelopmental disorders, such as eye tracking dysfunction in schizophrenia, are caused by unknown genetic mechanisms. Identifying these critical gene networks for sensory motor responsiveness in the visual system is one key to developing targeted early diagnostic and preventative strategies for the symptoms of these disorders that make the world a difficult place to navigate for those afflicted by them. My long-term goal is to characterize causative genetic mechanisms for neurodevelopmental disorders-related phenotypes using zebrafish as a model system. This powerful genetic model provides a unique opportunity as an easily accessible vertebrate with a comparatively “simple” nervous system, rapid neurodevelopment, many orthologues of human disease-related genes, and defined and tractable behavioral responses to visual stimuli. We can begin to study specific classes of neurons based on their molecular identity and function from the moment that they are born in the embryo through adulthood in rapid time compared to other vertebrate models. My previous work and that of others revealed for the first time the molecular identity of key interneurons that mediate sensory processing and reflexive control in the mouse and zebrafish auditory system. These neurons express the transcription factor Genomic Screen Homeobox 1 (Gsx1), and I sought to determine the role that Gsx1 plays in the development of neural circuits for sensory processing across the CNS. Upon examination of targeted gsx1 zebrafish mutants, we found profound defects in neuronal differentiation and axon guidance in the developing visual system. Despite its documented expression in the developing visual system in mouse and zebrafish, no research has been performed to date to examine the role that Gsx1 plays in development and function of visual neural circuits. Given the importance of transcriptional mechanisms for neural circuit development in sensory systems and the proposed ability to target key players in these large gene networks to treat diseases, we seek to fill this gap in knowledge. Aim 1 of this proposal will determine the consequences of mutating gsx1 on innate visually mediated behaviors and cell fate determination in the zebrafish pretectum and the eye. The experiments described in Aim 2 will identify the cellular mechanisms by which Gsx1 regulates arborization of axons in the pretectum that connect the eyes to the brain. We will be able to perform these experiments and analyze and validate the large amount of data that will be generated under the expert guidance of the Visual Function & Morphology Core, as well as the WVU Genomics Core Facility and the Bioinformatics Core Facility. This research will provide insight into the complex genetic etiology of neurodevelopmental disorders in which patients have comorbid defects in sensory processing. In addition, our studies will provide an abundance of data that can be utilized to support future research projects that align well with the development of visual function.