Pannexin-1 channel activity regulates neurogenesis and cell survival in the developing cortex

Mutations in genes encoding a range of ion-conducting proteins disrupt development of the cerebral cortex in humans, often causing polymicrogyria (PMG), yet how ion conduction guides the development of cortical architecture is not clear. Here, we describe three individuals with brain malformations including PMG and microcephaly in whom de novo, missense mutations were identified in PANX1 - encoding an ATP and ion conducting channel. We show that these PMG-associated PANX1 mutations (p.D14H, p.M37R, and p.N338T) disrupt normal glycosylation and confer gain-of-function with respect to ATP release and channel conductance. In vivo modeling of PANX1 mutant forms in cortical progenitor cells demonstrated disrupted cell migration and cell fate, including excess cell death in both mice and ferret models. Modeling the N338T allele in induced pluripotent stem cell (iPSC)-derived neurons further revealed how conductance changes lead to functional consequences of increased excitability and synchronicity. Our results show that normal PANX1 function contributes to cortical structure through regulation of ion conductance and ATP release and provides insight into how these processes influence corticogenesis and cytoarchitecture more broadly.