Fig. 6: Model for TMCO1 deficiency-induced agenesis of corpus callosum (AgCC) and MEKi-restored corpus callosum (CC) formation.

A The Tmco1^−/− brains exhibit severe CC defect during E14.5-E17.5. B Compared to wild-type embryonic brains with normal CC extension (B, upper right), the abnormal Ca²⁺ homeostasis induced by TMCO1 deficiency leads to supernormal Ca²⁺ signaling, over-activation of the FGF/ERK signaling at the midline, excessive migration of glial cells from GW to IG, and overpopulation of glial cells in the IG (B, lower left). Then the robust Slit2 signals secreted by IG glial cells repulse the callosal axon navigation before crossing the midline, leading to a halted extension of callosal axons and severe AgCC (B, lower left). Clinical MEK inhibitors efficiently reduce the excessive migration of glial cells from GW to IG, rebuild the Slit2 gradient balance between GW to IG, and restore the normal CC extension across the midline in Tmco1^−/− brains (lower right). These findings highlight a novel role of Ca²⁺ homeostasis maintained by TMCO1 in orchestrating the midline glial structure and CC formation during embryonic neurodevelopment, and provide a promising prevention strategy to relieve the related AgCC in patients.