Department of Neurobiology, Stanford University School of Medicine, Stanford, United States; Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States
Christos Haveles
Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States
Arpana Arjun
Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States; Graduate Program in Developmental and Stem Cell Biology, University of California, San Francisco, San Francisco, United States
Eli & Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, United States
Anshul Rana
Graduate Program in Biochemistry, Stanford University School of Medicine, Stanford, United States
Thomas Portmann
Department of Neurobiology, Stanford University School of Medicine, Stanford, United States
Department of Neurobiology, Stanford University School of Medicine, Stanford, United States; Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, United States
Theo D Palmer
Department of Neurosurgery, Stanford University School of Medicine, Stanford, United States
The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD.
