PRDM16 regulates a temporal transcriptional program to promote progression of cortical neural progenitors

Abstract

Radial glia (RG) in the neocortex sequentially generate distinct subtypes of projection neurons, accounting for the diversity and complex assembly of cortical neural circuits. Mechanisms that drive the rapid and precise temporal progression of RG are beginning to be elucidated. Here we reveal that the RG-specific transcriptional regulator PRDM16 promotes the transition of early to late phase of neurogenesis in the mouse neocortex. Loss of Prdm16 delays the timely progression of RG, leading to defective cortical laminar organization. Our genomic analyses demonstrate that PRDM16 regulates a subset of genes that are dynamically expressed between early and late neurogenesis. We show that PRDM16 suppresses target gene expression through limiting chromatin accessibility of permissive enhancers. We further confirm that critical target genes regulated by PRDM16 comprise neuronal specification genes, cell cycle regulators and molecules required for neuronal migration. These findings provide evidences to support that neural progenitors temporally shift gene expression program to achieve neural cell diversity.

PRDM16 functions as a co-repressor in the BMP pathway to suppress neural stem cell proliferation

“…1A ). Previously we reported that animals of the Prdm16 knockout (KO) null allele, Prdm16 cGT ( cGT ), show severely reduced ChP structure ( Fig 1B ) (Bjork et al, 2010; He et al, 2021; Strassman et al, 2017). In the Prdm16 KO mutant, expression of the ChP marker gene, Ttr , is not only reduced in the lateral ventricle (tChPs) but also in the fourth ventricle (hChP) ( Fig.…”

“…The PRDM16 protein is highly expressed in the nucleus of NSCs in embryonic brain tissues ( Fig. 1B , and (He et al, 2021)). Unexpectedly, the protein becomes nearly undetectable when primary NSCs are cultured in vitro ( Supplementary Fig.…”

“…There is no or only weak c-FOS binding to these regions in cells expressing Prdm16 , suggesting that there is cooperativity of SMAD and AP-1 facilitating each other’s binding when PRDM16 is absent. Alternatively, PRDM16 may suppress genomic accessibility of these regions for SMAD and AP-1 proteins, a function PRDM16 has in cortical NSCs (He et al, 2021).…”

“…PRDM16 has versatile functions at the molecular level. It regulates chromatin accessibility and epigenetic states of its bound enhancers (Baizabal et al, 2018; He et al, 2021), and depending on the associated cofactors, PRDM16 can repress or activate gene expression. This poses a challenge when targeting PRDM16 is a therapeutic strategy in disease treatment because undesired outcome may occur.…”

Timing as a Mechanism of Development and Evolution in the Cerebral Cortex

“…Loss of Prdm16. which regulates genes that are dynamically expressed between early and late neurogenesis, results in the extended production of deep layer neurons into periods when progenitors would usually be producing more superficial Brain Behav Evol 2022;97:8-32 DOI: 10.1159/000521678 neurons [He et al, 2021]. A recent article reported that opposing gradients of microRNAs (miR-9, miR-128 and Let-7) are expressed in progenitors throughout development, and that transient alterations of their expression can shift neuron production from early-to-later born fates and vice versa [Shu et al, 2019].…”