Mechanisms underlying neuronal enhancer specification during postnatal CNS development

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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.