Como Christina N, O'Rourke Rebecca, Winkler Caitlin, Mitchell Danae, Tran Luuli, Lorberbaum David, Sussel Lori, Franco Santos, Siegenthaler Julie
University of Colorado Anschutz Medical Campus, Department of Pediatrics, Section of Developmental Biology, Aurora, CO 80045, USA; University of Colorado Anschutz Medical Campus, Neuroscience Graduate Program, Aurora, CO 80045, USA.
University of Colorado Anschutz Medical Campus, Department of Pediatrics, Section of Developmental Biology, Aurora, CO 80045, USA.
Cell Rep. 2025 May 27;44(5):115637. doi: 10.1016/j.celrep.2025.115637. Epub 2025 Apr 29.
The meninges act as a regulator of brain development by secreting ligands that act on neural cells to regulate neurogenesis and neuronal migration. Meningeal-derived retinoic acid (RA) promotes neocortical neural progenitor cell cycle exit; however, the underlying molecular mechanism is unknown. Here, we used spatial transcriptomics and profiling of retinoic acid receptor α (RARα) DNA binding in Foxc1-mutant embryos that lack meninges-derived signals to identify potential neurogenic transcriptional mechanisms of RA signaling in telencephalic neural progenitors. This identified upregulation of Sox2 and Notch pathway genes, and RARα binds to the Sox2ot promoter, a long noncoding RNA that regulates Sox2 expression. Our experiments using maternal RA treatment and in utero electroporation in Foxc1 mutants support that meningeal-derived RA promotes neurogenesis by suppressing Notch signaling, a progenitor self-renewal pathway. Our findings elucidate a previously unknown mechanism of how meningeal RA coordinates neocortical development and provide insight into how defects in meningeal development may cause neurodevelopmental disorders.
脑膜通过分泌作用于神经细胞以调节神经发生和神经元迁移的配体，从而充当大脑发育的调节因子。脑膜来源的视黄酸（RA）促进新皮质神经祖细胞退出细胞周期；然而，其潜在的分子机制尚不清楚。在这里，我们使用空间转录组学以及对缺乏脑膜来源信号的Foxc1突变胚胎中视黄酸受体α（RARα）DNA结合的分析，来确定RA信号在端脑神经元祖细胞中的潜在神经发生转录机制。这确定了Sox2和Notch信号通路基因的上调，并且RARα与Sox2ot启动子结合，Sox2ot是一种调节Sox2表达的长链非编码RNA。我们在Foxc1突变体中使用母体RA处理和子宫内电穿孔的实验支持，脑膜来源的RA通过抑制Notch信号（一种祖细胞自我更新途径）来促进神经发生。我们的研究结果阐明了脑膜RA如何协调新皮质发育的先前未知机制，并为脑膜发育缺陷如何导致神经发育障碍提供了见解。
