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

使用斑马鱼研究视觉神经回路发育和功能的新型转录机制

• 批准号: 10593144
• 负责人: SADIE A BERGERON
• 金额: $ 29.94万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-20 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593144
• 关键词: Ablation; Adult; Affect; Auditory system; Axon; Behavior; Behavioral; Bioinformatics; Biological Models; Brain; Cells; Centers of Research Excellence; Clinical; Complex; Core Facility; Data; Defect; Development; Disease; Electroretinography; Embryo; Ephrins; Etiology; Eye; Eye Movements; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Genetic Transcription; Genomics; Glutamates; Goals; Homeobox; Human; Human Genome; Interneurons; Knock-out; Knowledge; Link; Measures; Mediating; Mentors; Microscopy; Modeling; Molecular; Molecular Genetics; Morphology; Motor; Mus; Mutate; Nervous System; Neural Pathways; Neuroanatomy; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Neurophysiology - biologic function; Orthologous Gene; Patients; Pharmacology; Phenotype; Play; Positioning Attribute; Presynaptic Terminals; Prevention strategy; Reporting; Research; Research Project Grants; Retinal Ganglion Cells; Rodent; Role; Saccades; Schizophrenia; Sensory; Specific qualifier value; Structure; Symptoms; Techniques; Tectum Mesencephali; Testing; Time; Vertebrates; Vision; Visual; Visual System; Work; Zebrafish; axon guidance; behavior test; behavioral response; cell type; comorbidity; comparative; diagnostic strategy; experimental study; gene network; genome wide association study; glutamatergic signaling; human disease; in vivo; insight; mRNA Expression; mutant; neural circuit; neurodevelopment; neuromechanism; neurotransmission; novel; programs; protein expression; response; sensory system; superior colliculus Corpora quadrigemina; synaptogenesis; transcription factor; vision development; vision science; visual processing; visual stimulus; visual tracking

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.

项目003(486)：研究视觉神经回路发育和转录的新机制 使用斑马鱼、Bergeron、PL的功能 项目摘要/摘要 与神经发育障碍相关的神经解剖学和行为变化，如眼球跟踪 精神分裂症的功能障碍，是由未知的遗传机制引起的。识别这些关键基因 视觉系统中感觉运动反应的网络是早期形成靶向的关键之一 对这些使世界陷入困境的疾病症状的诊断和预防策略 为那些受他们折磨的人导航。我的长期目标是描述致病遗传机制的特征 以斑马鱼为模型系统的神经发育障碍相关表型。这种强大的基因 模型提供了一个独特的机会，因为它是一种容易接近的脊椎动物，具有相对简单的神经 系统，快速的神经发展，人类疾病相关基因的许多同源基因，并定义和处理 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，基于它们 从它们在胚胎中出生的那一刻起到成年后的分子身份和功能 与其他脊椎动物模型相比，时间更短。我之前的工作和其他人的工作第一次揭示了 介导小鼠感觉加工和反射控制的关键中间神经元的分子特性 斑马鱼的听觉系统。这些神经元表达转录因子基因组屏幕同源框1(Gsx1)， 我试图确定Gsx1在感觉处理的神经回路发展中所起的作用 横跨中南欧。在对目标gsx1斑马鱼突变体的检查中，我们发现神经元存在严重缺陷。 视觉系统发育中的分化和轴突引导。尽管有文档记录了它在 在小鼠和斑马鱼身上开发视觉系统，到目前为止还没有进行任何研究来检验这种作用 Gsx1在视觉神经回路的发育和功能中发挥作用。考虑到转录的重要性 感觉系统中神经回路发育的机制和建议的针对关键角色的能力 这些庞大的基因网络用于治疗疾病，我们寻求填补这一知识空白。本提案的目标1将 确定突变的gsx1对先天视觉调节行为和细胞命运的影响 在斑马鱼的胎盘和眼睛里。目标2中描述的实验将确定细胞机制。 Gsx1通过它来调节大脑发育前连接眼睛和大脑的轴突的树枝形成。我们会的 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。这项研究将提供对复杂的遗传病因的洞察力。 神经发育障碍的患者在感觉处理方面有共同缺陷。此外，我们的 研究将提供丰富的数据，可以用来支持未来的研究项目，这些项目很好地结合在一起 随着视觉功能的发展。