Neurogenetic Mechanisms Controlling Functional Maturation of Neural Circuits and Behavior

项目摘要/摘要 所有的动物都经历了从幼年到成年的精心安排的过渡过程。这一转变带来了深刻的变化 在神经系统中，在人类中，是一段对各种疾病高度脆弱的时期，包括 精神分裂症、双相情感障碍、物质使用障碍和其他神经精神疾病。当一个伟大的人 Deal对这段时间内大脑发生的变化知之甚少，对 控制其发病的神经发生机制。在哺乳动物中，这种转变是由激活 HPG轴，但决定这种激活的适当时间的内部机制尚不清楚。 令人兴奋的是，最近的研究发现了与这一过程有关的基因之间出人意料的惊人相似之处。 在人类和线虫中。在这两个物种中，神经系统成熟的时间都是受调节的 由RNA结合蛋白LIN-28和一个鲜为人知的Makorins蛋白家族组成。我们最近 在线虫中的研究发现，Lin-28和makorin LEP-2与一种新的长非编码一起作用 RNA，lep-5，控制神经系统从幼年成熟到成熟期的时间。这表明， LEP-2-LEP-5-LIN-28定时模块可能是一种古老的成熟调节器，并提供了卓越的 利用线虫遗传学的力量来剖析其工作机制的机会。在这个项目中， 我们将(1)系统地鉴定线虫中发生的转录和功能变化 (2)开发和使用新的神经遗传学工具来确定 LncRNA lep-5调节这一过程的机制；以及(3)决定线虫和线虫如何 哺乳动物的Makorins在神经系统成熟过程中发挥作用。通过将非凡的试验性 线虫对这一重要而未被充分研究的生物学问题的适应性，这项研究将提供 对控制这一主要发育的内部神经元计时机制的重要新见解 过渡。

PROJECT SUMMARY/ABSTRACT All animals undergo a carefully timed transition from juvenile to adult. This transition entails profound changes in the nervous system and, in humans, is a period of heightened vulnerability to a variety of disorders, including schizophrenia, bipolar disorder, substance use disorders, and other neuropsychiatric conditions. While a great deal is known about the changes that happen in the brain during this time, far less is understood about the neurogenetic mechanisms that control its onset. In mammals, this transition is initiated by the activation of the HPG axis, but the internal mechanisms that determine the appropriate time for this activation are unknown. Excitingly, recent work has identified unexpected, striking parallels between genes implicated in this process in humans and in the nematode C. elegans. In both species, the timing of nervous system maturation is regulated by the RNA-binding protein LIN-28 and a poorly understood family of proteins called Makorins. Our recent work in C. elegans has found that LIN-28 and the Makorin LEP-2 act together with a novel long non-coding RNA, lep-5, to control the timing of juvenile-to-adult maturation of the nervous system. This indicates that the lep-2–lep-5–lin-28 timing module may be an ancient regulator of maturation, and provides an outstanding opportunity to use the power of C. elegans genetics to dissect the mechanisms by which it works. In this project, we will (1) systematically identify the transcriptomic and functional changes that take place in the C. elegans nervous system during juvenile-to-adult maturation; (2) develop and use new neurogenetic tools to determine the mechanism by which the lncRNA lep-5 regulates this process; and (3) determine how C. elegans and mammalian Makorins function in nervous system maturation. By bringing the exceptional experimental tractability of C. elegans to this important and understudied biological problem, this research will provide important new insights into the internal neuronal timing mechanisms that control this major developmental transition.