Dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons via GSK3β

Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, encodes a multifunctional protein implicated in various aspects of neuronal development. However, the precise role of DISC1 in neuronal polarization has remained elusive. Here, we show that dual phosphorylation of DISC1 at Ser58 and Ser713 regulates polarization of cortical neurons. Expression of phosphodead human DISC1 (hDISC1AA) delays the morphological transition from multipolar to uni/bipolar stages in mouse cortical neuronal cultures. hDISC1AA-knockin mice exhibit misoriented axon initial segments of cortical projecting neurons, reduced corpus callosum thickness, and schizophrenia-like behavior. Moreover, GSK3β activity is increased in the cortices of these knockin mice, and embryonic administration of GSK3β inhibitor effectively rescues aberrant axon initial segment and corpus callosum, as well as their behavioral deficits. Our findings support a molecular model wherein dephosphorylation of DISC1 at both Ser58 and Ser713 leads to enhanced GSK3β activity and subsequent inhibition of axon formation, potentially representing a key pathogenic mechanism underlying psychiatric disorders related to DISC1 dysfunction.