# Mechanisms underlying neuronal enhancer specification during postnatal CNS development

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $649,593

## Abstract

The mature central nervous system (CNS) is sculpted by the combined effects of intrinsic genetic programs and
dynamic environmental input, yet the precise manner by which these two processes collaborate to give rise to
the functional diversity of the mature nervous system remains to be fully explored. Using transgenic approaches
that allow for the purification of sparse neuronal subtypes, we find that lineage-committed cortical interneurons
undergo dynamic changes in gene expression in the early postnatal period, including the downregulation of
genes governing cell proliferation and migration as well as the concomitant upregulation of subtype-specific
genes important for mature neuronal function. We recently discovered that this postnatal transition in
transcription state is mediated by the licensing and decommissioning of thousands of cis-regulatory enhancer
elements across the genome. In the course of defining the regulatory elements that orchestrate these
transcriptional changes, we have uncovered a possible role for the AP-1 (Fos/Jun) family of stimulus-inducible
transcription factors (TFs) in promoting neuronal maturation through the de novo selection of sets of neuronal
subtype-specific enhancer elements, suggesting that external cues from the environment in early life have an
instructive role in shaping mature neuronal identities. To gain further insight into the mechanisms mediating
early postnatal enhancer selection and its contribution to neural circuit maturation and function, we propose (1)
to assess the role of sensory-driven activity in postnatal neuronal enhancer selection, (2) to characterize the
molecular mediators of postnatal enhancer selection, and (3) to test the contribution of enhancer remodeling to
postnatal neuronal maturation. It is our hope that the proposed experiments will yield a better understanding of
the molecular mechanisms underlying enhancer selection in the developing CNS, further illuminate how cell-intrinsic and -extrinsic mechanisms coordinate to drive mature circuit function, and ultimately provide new
opportunities for the development of therapeutic strategies to combat a subset of neurodevelopmental disorders.

## Key facts

- **NIH application ID:** 9942983
- **Project number:** 1R01NS115965-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** MICHAEL ELDON GREENBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $649,593
- **Award type:** 1
- **Project period:** 2020-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942983

## Citation

> US National Institutes of Health, RePORTER application 9942983, Mechanisms underlying neuronal enhancer specification during postnatal CNS development (1R01NS115965-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942983. Licensed CC0.

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