Prdm16 and Vcam1 regulate the postnatal disappearance of embryonic radial glia and the ending of cortical neurogenesis

Abstract

Embryonic neural stem cells (NSCs, i.e., radial glia) in the ventricular-subventricular zone (V-SVZ) generate the majority of neurons and glia in the forebrain. Postnatally, embryonic radial glia disappear and a subpopulation of radial glia transition into adult NSCs. As this transition occurs, widespread neurogenesis in brain regions such as the cerebral cortex ends. The mechanisms that regulate the postnatal disappearance of radial glia and the ending of embryonic neurogenesis remain poorly understood. Here, we show that PR domain-containing 16 (Prdm16) promotes the disappearance of radial glia and the ending of neurogenesis in the cerebral cortex. Genetic deletion of Prdm16 from NSCs leads to the persistence of radial glia in the adult V-SVZ and prolonged postnatal cortical neurogenesis. Mechanistically, Prdm16 induces the postnatal reduction in Vascular Cell Adhesion Molecule 1 (Vcam1). The postnatal disappearance of radial glia and the ending of cortical neurogenesis occur normally in Prdm16-Vcam1 double conditional knockout mice. These observations reveal novel molecular regulators of the postnatal disappearance of radial glia and the ending of embryonic neurogenesis, filling a key knowledge gap in NSC biology.

PRDM16 co-operates with LHX2 to shape the human brain

“…Histological and transcriptomic analysis of human organoids suggests a PRDM16 control of various aspects of neural stem cell biology including progenitor proliferation, transition of apical PAX6 + RG progression to basal HOPX + RG, aspects of cell adhesion, and migration. This is consistent with previous findings in mice showing that PRDM16 promotes cortical RG lineage progression into ependymal cells or adult neural stem cells [ 15 , 16 ]. Future experiments with more sophisticated human organoids systems that allow the study of PRDM16’s role in the generation of basal RG, neuronal migration that ultimately contribute to the expansion of the human brain will be necessary for addressing this question.…”

“…Our organoid data are consistent with previous findings that, in the embryonic mouse cortex, the absence of Prdm16 decreases the number and cycling of Eomes progenitors and increases cell cycle exit. It is also consistent with a recent paper suggesting that the absence of Prdm16 leads to the persistence of RG into late postnatal stages [ 16 ]. The increase was observed only in apical progenitors but not in the basal progenitors.…”

“…Loss of PRDM16 in mice is associated with defects in cell migration that result in the formation of neuronal heterotopias that persist into adulthood [ 16 , 41 ]. Interestingly, neuronal heterotopias is a common cause of seizures in humans [ 57 , 58 ].…”

“…6F ). Loss of either transcription factor upregulated neurogenesis, but its effect on progenitor identity was different in nature; while loss of PRDM16 leads to increased PAX6 + cells and prolonged radial glial lifetime in the mouse brain [ 16 ], loss of LHX2 in the mouse leads to reduced Pax6 expression and to a reduced number of PAX6 + cells [ 54 ]. This discrepancy might result from the expression of genes differentially regulated by PRDM16 and LHX2.…”

A Single-Cell Transcriptomic Analysis of the Mouse Hippocampus After Voluntary Exercise

“…Moreover, Dlx1, another highly active InN2 regulon that plays a role in regulating the functional longevity of GABAergic interneurons in the hippocampus, regulates Prdm16 and drives the expression of Prdm16-regulated Meis2 gene. Interestingly, a recent study also indicated that high Prdm16 expression is essential in promoting the disappearance of radial glia and the ending of cortical neurogenesis in the postnatal mouse brain [131]. Collectively, these findings, supported by the existing literature, allowed us to hypothesize that InN2 cells characterized by high Prdm16 expression could represent a specific developmental stage during adult neurogenesis captured only in cells from sedentary mice, possibly as a result of faster maturation of these Prdm16-high neurons upon exercise.…”