Graduate Program in Cell Biology, Stem Cells and Development, University of Colorado Graduate School - Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pediatrics, Section of Developmental Biology, University of Colorado School of Medicine - Anschutz Medical Campus, Aurora, CO 80045, USA.
Development. 2019 Mar 7;146(5):dev170068. doi: 10.1242/dev.170068.
During neocortical development, neurons are produced by a diverse pool of neural progenitors. A subset of progenitors express the gene and are fate restricted to produce certain neuronal subtypes; however, the upstream pathways that specify these progenitor fates remain unknown. To uncover the transcriptional networks that regulate expression in the forebrain, we characterized a conserved enhancer that recapitulates expression specifically in the cortical hem. Using a bioinformatic approach, we identified putative transcription factor (TF)-binding sites for cortical hem-patterning TFs. We found that the homeobox TF Lmx1a can activate the enhancer Furthermore, we showed that Lmx1a-binding sites were required for enhancer activity in the cortical hem Mis-expression of Lmx1a in hippocampal progenitors caused an increase in enhancer activity outside the cortical hem. Finally, we compared several human enhancers with cortical hem-restricted activity and found that recurrent Lmx1a-binding sites are a top shared feature. Uncovering the network of TFs involved in regulating expression will increase our understanding of the mechanisms pivotal in establishing lineage fates in the developing forebrain.
在新皮层发育过程中，神经元由多种神经祖细胞产生。祖细胞的一部分表达 基因，并被命运限制产生特定的神经元亚型；然而，指定这些祖细胞命运的上游途径仍然未知。为了揭示调节前脑 表达的转录网络，我们对一个保守的 增强子进行了特征描述，该增强子特异性地在前脑皮质中重现 表达。我们使用生物信息学方法，确定了皮质图案形成 TF 的潜在转录因子 (TF)-结合位点。我们发现同源盒 TF Lmx1a 可以激活 增强子。此外，我们表明 Lmx1a 结合位点对于皮质中的增强子活性是必需的。Lmx1a 在海马祖细胞中的异位表达导致 增强子活性在皮质之外增加。最后，我们比较了几个具有皮质限制活性的人类增强子，发现反复出现的 Lmx1a 结合位点是一个共同的特征。揭示参与调节 表达的 TF 网络将增加我们对在发育前脑建立 谱系命运的关键机制的理解。
