The DNA Methyltransferase 1 (DNMT1) Controls the Shape and Dynamics of Migrating POA-Derived Interneurons Fated for the Murine Cerebral Cortex

Abstract

The proliferative niches in the subpallium generate a rich cellular variety fated for diverse telencephalic regions. The embryonic preoptic area (POA) represents one of these domains giving rise to the pool of cortical GABAergic interneurons and glial cells, in addition to striatal and residual POA cells. The migration from sites of origin within the subpallium to the distant targets like the cerebral cortex, accomplished by the adoption and maintenance of a particular migratory morphology, is a critical step during interneuron development. To identify factors orchestrating this process, we performed single-cell transcriptome analysis and detected Dnmt1 expression in murine migratory GABAergic POA-derived cells. Deletion of Dnmt1 in postmitotic immature cells of the POA caused defective migration and severely diminished adult cortical interneuron numbers. We found that DNA methyltransferase 1 (DNMT1) preserves the migratory shape in part through negative regulation of Pak6, which stimulates neuritogenesis at postmigratory stages. Our data underline the importance of DNMT1 for the migration of POA-derived cells including cortical interneurons.

DNMT1 modulates interneuron morphology by regulatingPak6expression through crosstalk with histone modifications

“…Brain development is a complex process through which immature cortical GABAergic interneurons undergo a prolonged period of post-mitotic differentiation and maturation [5,6,[17][18][19][20][21]. The long-range tangential migration from their subpallial sites of origin, including the medial and caudal ganglionic eminences as well as the preoptic area (POA) [22][23][24][25][26][27][28][29][30], into cortical areas represents a critical developmental step. Proper migration relies on the adaption and preservation of a typical migratory morphology capable for directional adjustments induced by extrinsic cues, as well as the maintenance of their viability [29,[31][32][33][34][35][36][37][38][39].…”

“…The long-range tangential migration from their subpallial sites of origin, including the medial and caudal ganglionic eminences as well as the preoptic area (POA) [22][23][24][25][26][27][28][29][30], into cortical areas represents a critical developmental step. Proper migration relies on the adaption and preservation of a typical migratory morphology capable for directional adjustments induced by extrinsic cues, as well as the maintenance of their viability [29,[31][32][33][34][35][36][37][38][39]. The orchestration of the underlying complex and dynamic subcellular processes requires flexible gene regulation [40][41][42].…”

“…Epigenetic mechanisms like DNA methylation and histone tail modifications provide in part higher ordered regulatory features allowing for adaptive gene expression modifying developmental programs in response to external stimuli [40][41][42][43][44][45]. In addition to cytosine methylation in dividing progenitors, the DNA methylation-dependent and independent functions of the DNA methyltransferase 1 (DNMT1) seem to regulate transcription in developing as well as adult neurons [29,43,44,46].…”

“…In this context, we previously reported in Pensold et al (2016) [29] that DNMT1 promotes the migration and survival of Hmx3-expressing cortical interneurons generated in the preoptic area (POA) by repressing Pak6 expression, coding for a p21-activated serine/threonine protein kinase [47]. Conditional deletion of Dnmt1 causes increased expression levels of Pak6, which are associated with morphological alterations of migrating interneurons characterized by higher cellular complexity and increased cell death rates.…”

“…Conditional deletion of Dnmt1 causes increased expression levels of Pak6, which are associated with morphological alterations of migrating interneurons characterized by higher cellular complexity and increased cell death rates. This significantly reduces the number of interneurons reaching the cortex [29]. However, the underlying mechanism by which DNMT1 represses Pak6 gene expression remains unclear and seems independent of direct DNA methylation of the Pak6 locus or of genes encoding for potential regulatory factors [29].…”