Investigating the Role of cnb-1 and chpf-1 in GABA DD Motor Neuron Remodeling and Synapse Maintenance

项目摘要 在人脑发育期间，突触连接经历密集的重新布线，以形成 成熟的电路。人类发育重塑的中断与神经疾病有关，如 精神分裂症和自闭症谱系障碍。这个项目的目标是确定保守的机制， 直接突触重塑。遗传的简便性，加上更简单的组织和不变性 无脊椎动物神经系统的结构为神经元重塑的研究提供了强大的优势。我的 主要研究线虫内GABA能背侧D类(DD)运动神经元的重塑 秀丽隐杆线虫。以往的研究主要集中在突触前终末的重构上。在……里面 相比之下，我的初步工作重点是了解指导消除 突触后受体在重构过程中的作用。突触后区域。弗朗西斯实验室之前证明了 同源结构域转录因子Dve-1是GABA神经元消除突触所必需的。我的作品 聚焦于两个可能的DVE-1靶点，钙调神经磷酸酶样手蛋白chp1/chpf-1和调节 钙调神经磷酸酶PPP3R1/CNB-1亚基，在Dve-1突变体中下调。我的初选 研究表明，CNB-1或CHPF-1的突变破坏了突触重塑过程中的突触消除。我的 拟议的工作将确定CNB-1的功能要求和行动地点，并确定 钙调神经磷酸酶和蛋白酶体功能对突触消除的贡献(目标1)。在目标2中，我 将定义chpf-1如何促进突触的消除和维持。在目标3中，我将确定其他 利用神经元特异性RNA序列研究DVE-1在重塑通路中的潜在靶点。我提议的工作将 促进我们对重塑和调节机制的理解，潜在地为 未来的探索。

Project Summary During development of the human brain, synaptic connections undergo intensive rewiring in order to form mature circuits. Disruption of developmental remodeling in humans is linked to neurological disorders such as schizophrenia and autism spectrum disorders. The goal of this project is to identify conserved mechanisms that direct synapse remodeling. The ease of genetics, couple with the simpler organization and invariant architecture of invertebrate nervous systems offer strong advantages for studies of neuronal remodeling. My work focuses on the remodeling of GABAergic dorsal D-class (DD) motor neurons in the nemaode Caenorhabditis elegans. Prior studies have largely focused on the remodeling of presynaptic terminals. In contrast, my preliminary work has focused on understanding mechanisms that direct the elimination of postsynaptic receptors during remodeling. post-synaptic domain. The Francis lab previously demonstrated that the homeodomain transcription factor dve-1 is required for synapse elimination in GABA neurons. My work focuses on two putative DVE-1 targets, the calcineurin-like EF-hand protein CHP1/chpf-1 and the regulatory subunit of CalciNeurin PPP3R1/cnb-1, that were shown to be downregulated in dve-1 mutants. My preliminary studies suggest that mutation of either cnb-1 or chpf-1 disrupt synapse elimination during remodeling. My proposed work will determine the functional requirement and site of action for cnb-1, and identify the contribution of calcineurin phosphatase and proteasomal function to synapse elimination (Aim 1). In Aim 2, I will define how chpf-1 contributes to synapse elimination and maintenance. In Aim 3, I will identify additional potential targets of dve-1 in the remodeling pathway by using neuron-specific RNA-seq. My proposed work will advance our understanding of remodeling and the mechanisms of regulation, potentially providing targets for future exploration.