Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queens University Belfast, Belfast BT9 7BL, UK.
CRTD-Center for Regenerative Therapies, School of Medicine, Technische Universität Dresden, 01307 Dresden, Germany.
Development. 2022 Feb 1;149(3). doi: 10.1242/dev.200250. Epub 2022 Feb 11.
Corticogenesis 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.
皮质发生由一系列同步事件组成，包括皮质祖细胞的命运转变、神经元迁移、特化和连接。NeuroD1 是一种基本螺旋-环-螺旋(bHLH)转录因子(TF)，有助于所有这些事件，但它如何协调这些独立的事件仍然未知。在这里，我们证明了 NeuroD1 的表达伴随着大量基因组位点上活性染色质的增加。有趣的是，这些位点的转录激活依赖于相邻 bHLH TF 基序的高密度，包括主要的 Tcf12。我们发现，在诱导表达跨越皮质祖细胞从增殖到神经发生分裂的水平的细胞中，Tcf12 的活性和表达水平很高。此外，Tcf12 与 NeuroD1 形成复合物，并共同占据 NeuroD1 靶基因座的一部分。这种 Tcf12-NeuroD1 协同作用对于获得活性染色质和靶向表达参与细胞迁移的基因是必不可少的。通过体内功能操作，我们进一步表明，在皮质发育过程中，Tcf12 对于新生神经元的正确迁移是必不可少的，因此对于皮质层状结构的正常形成也是必不可少的。
