The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis

Abstract

BackgroundAlterations in early steps of cortical circuit assembly are thought to play a critical role in vulnerability to schizophrenia (SZ), but the pathogenic impact of SZ-risk mutations on corticogenesis remains to be determined. DiGeorge syndrome critical region 2 (DGCR2) is located in the 22q11.2 locus, whose deletion is a major risk factor for SZ. Moreover, exome sequencing of individuals with idiopathic SZ identified a rare missense mutation in DGCR2, further suggesting that DGCR2 is involved in SZ. MethodsHere we investigated the function of Dgcr2 and the pathogenic impact of the SZ-risk DGCR2 mutation in mouse corticogenesis using in utero electroporation targeted to projection neurons. ResultsDgcr2 knockdown impaired radial locomotion and final translocation of projection neurons, leading to persistent laminar positioning alterations. The DGCR2 missense SZ-risk mutation had a pathogenic impact on projection neuron laminar allocation by reducing protein expression. Mechanistically, we identified Dgcr2 as a novel member of the Reelin complex, regulating the phosphorylation of Reelin-dependent substrates and the expression of Reelin-dependent transcriptional targets. ConclusionsOverall, this study provides biological evidence that the SZ-risk gene DGCR2 regulates critical steps of early corticogenesis possibly through a Reelin-dependent mechanism. Additionally, we found that the SZ-risk mutation in DGCR2 has a pathogenic impact on cortical formation by reducing protein expression level, suggesting a functional role for DGCR2 haploinsufficiency in the 22q11.2 deletion syndrome.