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.
Adolescence, the period of transition from childhood to adulthood, is a key life stage and a period of heightened vulnerability to a variety of mental health disorders. However, how the brain knows when to undertake this transition is almost completely mysterious. Using the powerful experimental accessibility of the nematode worm C. elegans, this research will identify the genetic mechanisms that act in the brain to control the timing of the juvenile-to-adult transition and this period of heightened vulnerability.
