The Sox2 regulatory region 42 produces enhancer RNAs that influence neuronal migration during cortical development

Abstract

Summary Precise regulation of neural progenitor states and neuronal positioning is essential for cortical development. Here, we identified Sox2 regulatory region 42 (SRR42), a regulatory region located 42 kb downstream of the Sox2 transcription start site that exhibits open chromatin, active histone modifications, and bidirectional transcription of enhancer RNAs (eRNAs). Using transgenic reporter mice, we found that SRR42 is active in neural progenitor cells in the developing cortex. CRISPR-Cas9-mediated deletion of SRR42 combined with single-cell multiome analysis revealed alterations in progenitor-state dynamics, neuronal migration, and cortical lamination without detectable changes in Sox2 expression. Furthermore, in vivo knockdown of SRR42-derived eRNAs impaired neuronal migration. These findings identify SRR42-derived RNAs as regulators of neuronal migration during cortical development and highlight enhancer-associated transcription as a functional component of neurodevelopmental gene regulation.