Single-Cell Transcriptomics Reveals Regulators of Neuronal Migration and Maturation During Brain Development

Abstract

The correct establishment of inhibitory circuits is crucial for cortical functionality and defects during the development of γ-aminobutyric acid-expressing cortical interneurons contribute to the pathophysiology of psychiatric disorders. A critical developmental step is the migration of cortical interneurons from their site of origin within the subpallium to the cerebral cortex, orchestrated by intrinsic and extrinsic signals. In addition to genetic networks, epigenetic mechanisms such as DNA methylation by DNA methyltransferases (DNMTs) are suggested to drive stage-specific gene expression underlying developmental processes. The mosaic structure of the interneuron generating domains producing a variety of interneurons for diverse destinations complicates research on regulatory instances of cortical interneuron migration. To this end, we performed single-cell transcriptome analysis revealing <i>Dnmt1</i> expression in subsets of migrating interneurons. We found that DNMT1 preserves the migratory morphology in part through transcriptional control over <i>Pak6</i> that promotes neurite complexity in postmigratory cells. In addition, we identified <i>Ccdc184</i>, a gene of unknown function, to be highly expressed in postmitotic interneurons. Single-cell mRNA sequencing revealed a positive correlation of <i>Ccdc184</i> with cell adhesion-associated genes pointing to potential implications of CCDC184 in processes relying on cell-cell adhesion-like migration or morphological differentiation of interneurons that deserves further investigations.