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

点击翻译按钮获取中文摘要

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.