Neurogenetic Mechanisms Controlling Functional Maturation of Neural Circuits and Behavior

项目总结/摘要 所有的动物都要经历一个从幼年到成年的精心安排的过渡期。这一转变需要深刻的变革 在神经系统和人类中，是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病症。虽然伟大的 关于这段时间大脑中发生的变化，我们知道的很少，关于这段时间大脑中发生的变化， 控制其发作的神经遗传机制。在哺乳动物中，这种转变是由激活 HPG轴，但内部机制，确定适当的时间，这种激活是未知的。 令人兴奋的是，最近的研究发现，与这一过程有关的基因之间存在意想不到的惊人相似之处， 人类和线虫C.优雅在这两个物种中，神经系统成熟的时间是受调节的， RNA结合蛋白LIN-28和一个鲜为人知的称为Makorins的蛋白质家族。我们最近 在C工作。elegans发现LIN-28和Makorin LEP-2与一种新的长非编码区一起起作用， RNA，lep-5，控制神经系统从幼年到成年的成熟时间。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， 利用C的力量。elegans遗传学来剖析它的工作机制。在这个项目中， 我们将（1）系统地鉴定C. elegans 神经系统在青少年到成人成熟;（2）开发和使用新的神经遗传学工具，以确定 lncRNA lep-5调节这一过程的机制;以及（3）确定C.线虫和 哺乳动物Makorins在神经系统成熟中起作用。通过带来卓越的实验性 C.易处理性这一重要的和未充分研究的生物学问题，这项研究将提供 重要的新的见解，内部神经元的定时机制，控制这一主要的发展 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.