Cortical folding is a highly regulated process involving amplification of neuroprogenitor cells, increased neurogenesis and migration of neurons along the tangential axis. Mice have smooth brain surface (lissencephaly) that evolved from loss of folding present in gyrencephalic (folded cortex) mammals. Here, Max Tischfield and colleagues investigate the signalling processes behind cortical folding in mice. First, the authors show that inactivating Twist1, a transcription factor, in the primitive meninges induces cortical folding in mice. The authors find that in the Twist1 mutant mice, cell proliferation in the meninges is reduced, leading to regionalised loss of Raldh2, an enzyme required for retinoic acid (RA) synthesis. This loss of Raldh2 in the dorsolateral meninges is first detected when folding begins. Then, the authors assess changes to neurogenesis as cortical folding happens, and observe regionalised differences in the levels of neurogenesis and changes to the tangential distribution of neurons. This leads to differential cortical expansion in different brain regions, resulting in cortical buckling and folding. Finally, the authors show that supplementing maternal RA can rescue imbalanced neurogenesis and lissencephaly in Twist1 mutant embryos. Overall, these findings suggest that Twist1 and balanced RA signalling from the meninges are important in maintaining neurogenesis and lissencephaly in mice.
