PCDH19 is a cell adhesion molecule belonging to the protocadherin subgroup within the cadherin superfamily. It is predominantly expressed in the nervous system. Heterozygous loss-of-function variants in the human X-linked gene PCDH19 lead to early infantile epileptic encephalopathy associated with varying degrees of intellectual disability and autistic features. PCDH19-related epilepsy shows an atypical pattern of inheritance, where heterozygous females
SummaryProtocadherins (PCDHs) are cell adhesion molecules that regulate many essential neurodevelopmental processes related to neuronal maturation, dendritic arbor formation, axon pathfinding, and synaptic plasticity. Bi-allelic loss-of-function variants inPCDH12are associated with several neurodevelopmental disorders (NDDs) such as diencephalic-mesencephalic dysplasia syndrome, cerebral palsy, cerebellar ataxia, and microcephaly. Despite the highly deleterious outcome resulting from loss of PCDH12, little is known about its role during brain development and disease. Here, we show that PCDH12 loss severely impairs cerebral organoid development with reduced proliferative areas and disrupted laminar organization. 2D models further show that neural progenitor cells lacking PCDH12 prematurely exit cell cycle and differentiate earlier when compared to wildtype. Furthermore, we show that PCDH12 regulates neuronal migration through a mechanism requiring ADAM10-mediated ectodomain shedding and membrane recruitment of cytoskeleton regulators. Our data demonstrate a critical and broad involvement of PCDH12 in cortical development, revealing the pathogenic mechanisms underlying PCDH12-related NDDs.
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