树突和轴突导向是神经环路形成的关键步骤。与轴突导向相比，我们对树突导向的机制还知之甚少。为了深入理解树突导向机制，我们利用秀丽线虫多树突分支的PVD神经元为模式，开展了遗传筛选并获得了多个kpc-1、hpo-30和dma-1等树突导向异常突变体。申请人的前期工作表明，KPC-1负调控DMA-1树突导向受体的蛋白水平；两个新颖的dma-1功能获得性突变造成与kpc-1功能缺失突变类似的树突导向缺陷。在此基础上，申请人拟综合利用遗传分析、活体成像、生化分析和单细胞转录组分析等多种手段，研究KPC-1和HPO-30如何通过调控DMA-1的膜泡运输而保证正确的树突导向，以及在时间维度上kpc-1和hpo-30本身的表达水平如何被动态调控的机制。树突发育异常与自闭症和精神分裂症等多种神经疾病密切相关。本课题将帮助我们更好的理解树突发育异常相关疾病的致病机理，和为开发神经环路功能性重建等提供理论支持。

Dendrite and axon guidance are critical for neural circuit assembly. Compared to axon guidance, it remains less well-understood how dendrites are precisely guided during development. To better understand the dendrite guidance mechanisms, we carried out large-scale genetic screens using C. elegans multi-dendritic PVD neurons as a model. We have successfully isolated multiple dendrite guidance abnormal mutants, including mutations in kpc-1/furin, hpo-30/claudin and dma-1/LRR-TM. We found that KPC-1 negatively regulates the protein level of dendritic guidance receptor DMA-1. Two dma-1 gain-of-function mutants mimic the dendritic guidance defects of kpc-1 loss-of-function mutants. In this proposal, we will combine genetic analysis, live cell imaging, biochemical analysis and single cell RNA sequencing to investigate how KPC-1 and HPO-30 regulate membrane transport of DMA-1 receptor, as well as how the expressions of kpc-1 and hpo-30 are temporally regulated during dendrite guidance. Abnormal dendrite development is closely associated with neurological diseases such as autism and schizophrenia. Our study will not only help us to better understand the mechanisms underlying these diseases, but also provide useful information to functionally re-built neural circuit in vivo.