Meningeal-derived retinoic acid regulates neurogenesis via suppression of Notch and Sox2

Abstract

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 ligands to identify the neurogenic transcriptional mechanisms of RA signaling in telencephalic neural progenitors. We determined that meningeal-derived RA controls neurogenesis by suppressing progenitor self-renewal pathways Notch signaling and the transcription factor Sox2. We show that RARα binds in the Sox2ot promoter, a long non-coding RNA that regulates Sox2 expression, and RA promotes Sox2ot expression in neocortical progenitors. Our findings elucidate a previously unknown mechanism of how meningeal RA coordinates neocortical development and insight into how defects in meningeal development may cause neurodevelopmental disorders.

Spatiotemporal analysis of gene expression in the human dentate gyrus reveals age-associated changes in cellular maturation and neuroinflammation

“…ALDH1A2 and other genes that encode enzymes that synthesize retinoic acid (RA) 82 are enriched in the human GCL, but are not highly expressed in the adult mouse DG 60 . RA promotes synaptic plasticity in DG neurons 83 , and it also affects DG neurogenesis in a biphasic manner - depletion reduces neural differentiation and cell survival 84,85 while excess amounts reduce neural proliferation 86 . Given these established roles for ALDH1A2 and POSTN in GC plasticity and development, our data showing specificity of their expression in the human GCL renders these genes as prime candidates for follow up studies.…”