Clustered Protocadherins Emerge as Novel Susceptibility Loci for Mental Disorders

The clustered protocadherins (cPcdhs) are a subfamily of type I single-pass transmembrane cell adhesion molecules predominantly expressed in the brain. Their stochastic and combinatorial expression patterns encode highly diverse neural identity codes which are central for neuronal self-avoidance and non-self discrimination in brain circuit formation. In this review, we first briefly outline mechanisms for generating a tremendous diversity of cPcdh cell-surface assemblies. We then summarize the biological functions of cPcdhs in a wide variety of neurodevelopmental processes, such as neuronal migration and survival, dendritic arborization and self-avoidance, axonal tiling and even spacing, and synaptogenesis. We focus on genetic, epigenetic, and 3D genomic dysregulations of cPcdhs that are associated with various neuropsychiatric and neurodevelopmental diseases. A deeper understanding of regulatory mechanisms and physiological functions of cPcdhs should provide significant insights into the pathogenesis of mental disorders and facilitate development of novel diagnostic and therapeutic strategies.