Twist1 and balanced retinoic acid signaling act to suppress cortical folding in mice
Evolution of cortical folding in gyrencephalic animals enabled higher cognitive functions and complex behaviors. Gene expression patterns and signaling molecules that control cortical folding have only recently been described and thus are still not well understood. In transgenic mouse models with induced cortical folding, amplification of neuroprogenitor cells or loss of their adhesion from the apical ventricular surface leads to gyri formation, whereas decreased cell adhesion in migrating projection neurons causes abnormal neuronal clustering and development of cortical fissures that resemble sulci. We now report that loss of Twist1 expression in the primitive meninx results in cortical folding and sulci formation in the dorsolateral telencephalon. In developing sulcal regions, generation of apical and basal neuroprogenitor cells is normal. Instead, cell proliferation in the developing meninges is reduced, leading to loss of arachnoid fibroblasts that express Raldh2, an enzyme required for retinoic acid synthesis. Maternal retinoic acid supplementation rescues cortical folding and sulci formation. Our results suggest that balanced retinoic acid signaling from the meninges is required to maintain lissencephaly in mice, and in a manner independent from neuroprogenitor cell amplification.