# Epigenetic mechanisms regulating neuron production during cortical development > **NIH NIH P20** · SANFORD RESEARCH/USD · 2022 · $324,755 ## Abstract The cerebral cortex is the brain region underlying human higher cognitive functions, such as complex decisionmaking, reading and reasoning. These functions rely on networks of neurons mainly generated during embryonic development. During that developmental period, the balance between proliferation and differentiation of neural precursors (NPs) is critical for the generation of appropriate numbers of neurons. Therefore, disruptions of NP proliferation are at the origin of numerous neurodevelopmental disorders, such intellectual disabilities, autism, microcephaly and macrocephaly. Numerous cellular and molecular processes regulate proliferation vs differentiation decisions in NPs. In the present study, we wiPll focus on epigenetic mechanisms modulating the expression of proliferation and differentiation genes. To do this, we will focus on the transcription factor ZBTB7A, known to mediate chromatin accessibility in the regulatory regions of genes implicated in proliferation and differentiation. ZBTB7A has been implicated in many different systems, but its role in NPs during cortical development is completely unknown. However, the ZBTB7A gene is located in the 19p13.3 microlocus containing 3 genes, and whose duplication or deletion lead to microcephaly and macrocephaly, respectively. Our preliminary studies in the mouse show that altered expression of ZBTB7A in NPs leads to proliferation deficits with predicted outcomes matching those observed in the 19p13.3 syndrome. Altogether these findings make ZBTB7A an outstanding candidate to discover novel epigenetic mechanisms regulating the development of the cerebral cortex. In this study we will use mouse models mimicking ZBTB7A alterations in humans to characterize how altered expression of ZBTB7A impacts NP proliferation and the establishment of cortical architecture. In a second step, we will characterize ZBTB7A target genes in NPs using ChIP-seq coupled with RNA-seq. After validation of candidate genes using luciferase assays, we will attempt genetic rescue experiments to re-establish the phenotypes caused by altered ZBTB7A levels. In a third step we will further dissect the molecular mechanisms by which ZBTB7A regulates gene expression in NPs, focusing on ZBTB7A co-factors. To do this, we will use BioID to identify proteins operating in the vicinity of ZBTB7A in cortical NPs and we will use luciferase, ChIP-PCR and co-IP assays to understand the mechanism by which ZBTB7A can affect the recruitment of those co-factors to gene regulatory region, and thus impact gene expression. This project will advance the mission of the Pediatrics and Rare Diseases group at Sanford Research, while providing new insights into the epigenetic mechanisms regulating the development of the cerebral cortex, and how disruption of these mechanisms can lead to neuropediatric diseases. ## Key facts - **NIH application ID:** 10683534 - **Project number:** 5P20GM103620-10 - **Recipient organization:** SANFORD RESEARCH/USD - **Principal Investigator:** Louis-Jan Pilaz - **Activity code:** P20 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $324,755 - **Award type:** 5 - **Project period:** 2022-09-01 → 2025-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10683534 ## Citation > US National Institutes of Health, RePORTER application 10683534, Epigenetic mechanisms regulating neuron production during cortical development (5P20GM103620-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10683534. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*