# Neurogenetic Mechanisms Controlling Functional Maturation of Neural Circuits and Behavior

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $308,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10308518
- **Project number:** 5R01GM140415-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Douglas S Portman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $308,000
- **Award type:** 5
- **Project period:** 2020-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308518

## Citation

> US National Institutes of Health, RePORTER application 10308518, Neurogenetic Mechanisms Controlling Functional Maturation of Neural Circuits and Behavior (5R01GM140415-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10308518. Licensed CC0.

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