Gli2 Rescues Delays in Brain Development Induced by Kif3a Dysfunction

The primary cilium in neural stem cells plays distinct roles in different stages during cortical development. Ciliary dysfunctions in human (i.e., ciliopathy) cause developmental defects in multiple organs, including brain developmental delays, which lead to intellectual disabilities and cognitive deficits. However, effective treatment to this devastating developmental disorder is still lacking. Here, we first investigated the effects of ciliopathy on neural stem cells by knocking down Kif3a, a kinesin II motor required for ciliogenesis, in the neurogenic stage of cortical development by in utero electroporation of mouse embryos. Brains electroporated with Kif3a shRNA showed defects in neuronal migration and differentiation, delays in neural stem cell cycle progression, and failures in interkinetic nuclear migration. Interestingly, introduction of Gli1 and Gli2 both can restore the cell cycle progression by elevating cyclin D1 in neural stem cells. Remarkably, enforced Gli2 expression, but not Gli1, partially restored the ability of Kif3a-knockdown neurons to differentiate and move from the germinal ventricular zone to the cortical plate. Moreover, Cyclin D1 knockdown abolished Gli2's rescue effect. These findings suggest Gli2 may rescue neural stem cell proliferation, differentiation and migration through Cyclin D1 pathway and may serve as a potential therapeutic target for human ciliopathy syndromes through modulating the progression of neural stem cell cycle.