| First Author | Molinard-Chenu A | Year | 2018 |
| Journal | Biol Psychiatry | Volume | 83 |
| Issue | 8 | Pages | 692-706 |
| PubMed ID | 29305086 | Mgi Jnum | J:308607 |
| Mgi Id | MGI:6730384 | Doi | 10.1016/j.biopsych.2017.11.015 |
| Citation | Molinard-Chenu A, et al. (2018) The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis. Biol Psychiatry 83(8):692-706 |
| abstractText | BACKGROUND: Alterations 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. METHODS: Here 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. RESULTS: Dgcr2 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. CONCLUSIONS: Overall, 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. |
