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bioRxiv · 10.1101/2024.04.05.588348

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

Como, C. N.·O'Rourke, R.·Winkler, C.·Mitchell, D.·Tran, L. N.·Lorberbaum, D.·Sussel, L.·Franco, S. J.·Siegenthaler, J. A.
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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- (RAR) 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 RAR 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.

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Como, C. N., O'Rourke, R., Winkler, C., Mitchell, D., Tran, L. N., Lorberbaum, D., Sussel, L., Franco, S. J., Siegenthaler, J. A.. 2024-04-09. Meningeal-derived retinoic acid regulates neurogenesis via suppression of Notch and Sox2. https://doi.org/10.1101/2024.04.05.588348

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