14-3-3zeta modulates non canonical Shh signalling to control cortical interneuron development
Centre for Cancer Biology, University of South Australia.
Dysfunction in the formation and function of GABAergic cortical interneurons has been implicated as a central pathogenic mechanism in schizophrenia. 14-3-3ζ is part of a family of highly conserved intracellular proteins, that bind to the phosphoserine/theronine sites on target proteins and is highly expressed in the brain. Several findings in recent years implicate 14-3-3ζ as a candidate risk factor for schizophrenia including: 1) 14-3-3ζ is downregulated in post-mortem schizophrenic brain samples at the mRNA level; 2) 14-3-3ζ is downregulated across multiple neuroproteomic studies on schizophrenia patient samples; 3) linkage studies have implicated 14-3-3 family proteins in numerous neurodevelopmental disorders, and 4) genetic mutations in the gene encoding 14-3-3ζ have been found in schizophrenia patients. Previous studies have shown that 14-3-3ζ KO mice exhibit anatomical and behavioural traits akin to those seen in schizophrenia. Here we identify a novel role for 14-3-3ζ in interneuron development. We found a specific reduction in parvalbumin expressing interneurons throughout the cortex of 14-3-3ζ KO mice. Through a series of molecular, biochemical and morphological studies we further show that parvalbumin interneuron deficiency arises from defects in the specification and formation of interneurons during early brain development. Mechanistically, we found that 14-3-3ζ regulates non-canonical Shh signalling via controlling the activity of Rac1. Taken together, this work provides novel insight into the role of 14-3-3ζ in controlling interneuron development and identifies a novel role of 14-3-3ζ in the pathogenesis of schizophrenia.