Dendrite morphogenesis, function and regeneration

树突形态发生、功能和再生

• 批准号: 10063910
• 负责人: YUH NUNG JAN
• 金额: $ 55.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063910
• 关键词: Afferent Neurons; Ankyrin Repeat; Area; Axon; Biological Models; Defect; Dendrite Regeneration; Dendrites; Development; Diagnosis; Disease; Dissection; Down Syndrome; Drosophila genus; Esthesia; Foundations; Future; Genetic; Genetic Screening; Injury; Knowledge; Mammals; Mechanics; Mental disorders; Molecular; Morphogenesis; Morphology; Natural regeneration; Nervous system structure; Neurons; Neurosciences; Paper; Pathway interactions; Pattern; PubMed; Regenerative research; Solid; Structure; Touch sensation; autism spectrum disorder; axon guidance; axon regeneration; fly; insight; interest; mechanotransduction; mutant; nervous system disorder; neuronal circuitry; novel

Project Summary/Abstract For proper assembly of neuronal circuitry, axons have to be guided toward the correct targets and dendrites need to have the correct branching pattern and structural specialization. Despite considerable recent progress, much less is known about molecular mechanisms that control dendrite development as compared to those controlling axon guidance. About 15 years ago, our lab initiated a fruitful genetic dissection of dendrite development using Drosophila dendritic arborization (da) neurons as a model system. Multiple genetic screens and the ensuing analysis of dendrite mutants have yielded important insights about the molecular basis of dendrite development in Drosophila, including how axons and dendrites are made differently, how a neuron acquires its neuronal type specific morphology, how the dendrites of different neurons are organized relative to one another, how the size of a dendritic arbor is controlled, and how the pruning and remodeling of dendrites are regulated during development. Many of the molecular mechanisms controlling dendrite development have turned out to be conserved between Drosophila and mammals. Given that defects in dendrites are strongly associated with diseases such as Down syndrome and a subset of autism spectrum disorder, elucidating molecular pathways that control dendritic morphogenesis is not only of great interest in basic neuroscience but also important for the potential relevance to neurological disorders. As we continue to investigate the mechanisms that control dendrite morphogenesis, the knowledge we have gained provide a solid foundation for exploring some very interesting and understudied areas about dendrites: (1) The function of dendrites and the relationship between form and function. Drosophila da neurons are sensory neurons; all of them are mechano-sensitive. This has led us to venture into the study of mechano-sensation, the least well understood among our senses. Very few molecules have been firmly established as mechano-transduction channels. By using da neurons, we discovered that NompC is a bona fide mechano-transduction channel that enables the fly to sense gentle touch. We have also provided strong evidence that NompC is gated mechanically by a tethering mechanism that involves the Ankyrin repeats of NompC functioning as a gating spring. We propose to continue the in depth study of how NompC transduces force. Furthermore, because there are still many novel mechano-sensitive channels that remain to be discovered, we will use the fly sensory neuron as a model system to identify and study them. (2) Dendrite regeneration after injury. By using da neurons that are well suited for studying both axon regeneration and dendrite regeneration, we have been able to identify novel regulators of axon regeneration. Compare to axon regeneration, much less is known about dendrite regeneration (a recent PubMed search revealed over 1400 papers on axon regeneration but only 4 on dendrite regeneration to date). We are keen about uncovering mechanisms that control dendrite regeneration, an important but so far little studied problem.

项目概要/摘要 为了正确组装神经元电路，必须引导轴突朝向正确的目标和树突 需要具有正确的分支模式和结构专业化。尽管最近相当多 相比之下，人们对控制树突发育的分子机制知之甚少 那些控制轴突引导的人。大约 15 年前，我们的实验室启动了一项卓有成效的基因解剖 使用果蝇树突分枝（da）神经元作为模型系统进行树突发育。多种的 遗传筛选和随后对树突突变体的分析已经产生了关于树突突变体的重要见解 果蝇树突发育的分子基础，包括轴突和树突的形成方式 不同的是，神经元如何获得其神经元类型特定的形态，不同的树突如何 神经元是相对于彼此组织的，树突乔木的大小是如何控制的，以及如何 树突的修剪和重塑在发育过程中受到调节。许多分子机制 事实证明，控制树突发育的机制在果蝇和哺乳动物之间是保守的。给定 树突缺陷与唐氏综合症等疾病密切相关 自闭症谱系障碍，阐明控制树突形态发生的分子途径不仅是 对基础神经科学非常感兴趣，但对神经系统疾病的潜在相关性也很重要。 当我们继续研究控制树突形态发生的机制时，我们的知识 已经获得了为探索一些非常有趣和未充分研究的领域提供了坚实的基础 树突：（1）树突的功能以及形态与功能的关系。果蝇 神经元是感觉神经元；它们都是机械敏感的。这促使我们冒险进行研究 机械感觉，是我们的感官中最不为人所知的感觉。很少有分子被牢固地固定 建立为机械传导通道。通过使用 da 神经元，我们发现 NompC 是一个真正的 真实的机械传导通道，使果蝇能够感知轻柔的触摸。我们还提供了强有力的 有证据表明 NompC 通过涉及锚蛋白重复的束缚机制进行机械门控 NompC 用作门控弹簧。我们建议继续深入研究NompC如何转导 力量。此外，由于仍有许多新颖的机械敏感通道有待开发 发现后，我们将使用苍蝇感觉神经元作为模型系统来识别和研究它们。 (2)枝晶 受伤后的再生。通过使用非常适合研究轴突再生和 树突再生，我们已经能够识别轴突再生的新调节因子。与轴突比较 再生，人们对树突再生知之甚少（最近的 PubMed 搜索显示超过 1400 关于轴突再生的论文，但迄今为止只有 4 篇关于树突再生的论文）。我们热衷于揭开 控制枝晶再生的机制，这是一个重要但迄今为止很少研究的问题。