Abstract
ABSTRACTCorticogenesis consists of a series of synchronised events, including fate transition of cortical progenitors, neuronal migration, specification and connectivity. NeuroD1, a basic helix-loop-helix (bHLH) transcription factor (TF), contributes to all of these events, but how it coordinates these independently is still unknown. Here, we demonstrate that NeuroD1 expression is accompanied by a gain of active chromatin at a large number of genomic loci. Interestingly, transcriptional activation of these loci relied on a high local density of adjacent bHLH TFs motifs, including, predominantly, Tcf12. We found that activity and expression levels of Tcf12 were high in cells with induced levels of NeuroD1 that spanned the transition of cortical progenitors from proliferative to neurogenic divisions. Moreover, Tcf12 forms a complex with NeuroD1 and co-occupies a subset of NeuroD1 target loci. This Tcf12-NeuroD1 cooperativity is essential for gaining active chromatin and targeted expression of genes involved in cell migration. By functional manipulation in vivo, we further show that Tcf12 is essential during cortical development for the correct migration of newborn neurons and, hence, for proper cortical lamination.
Highlights
The brain is the most complex organ that has arisen in evolution, but exactly how this complexity is generated during development is still poorly understood
We demonstrated that NeuroD1 functions as a pioneer transcription factor (PTF) to remove repressive chromatin marks, and induce chromatin remodelling and activation of the target neuronal genes (Pataskar et al, 2016a)
We investigated how a pro-neural pioneer transcription factor (TF), NeuroD1, functions at a genome-wide level to induce active chromatin and gene expression, and coordinate specific cellular events during corticogenesis through its interaction with another basic helix-loop-helix (bHLH) TF: Tcf12
Summary
The brain is the most complex organ that has arisen in evolution, but exactly how this complexity is generated during development is still poorly understood. During embryonic development of the mammalian cortex, these programs initially promote neuroepithelial stem cells expansion at the apical boundary of the ventricular zone (VZ) that for this reason are called apical progenitors (APs) Changes in transcriptional and epigenetic programs are required to drive an increasing proportion of APs to switch from proliferative to differentiative divisions and generate either basal progenitors (BPs) that leave the VZ to form the subventricular zone (SVZ) or neurons (Basu et al, 2020). Within the CP, a correct cellular specification and layering must ensue for newborn neurons to form proper cortical lamination (Buchsbaum and Cappello, 2019)
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