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Biol Psychiatry. 2018 Apr 15;83(8):692-706. doi: 10.1016/j.biopsych.2017.11.015. Epub 2017 Nov 21.

The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis.

Author information

1
Department of Psychiatry, University of Geneva Medical School, Geneva, Switzerland; Department of Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva Medical Center, Geneva, Switzerland.
2
Department of Psychiatry, University of Geneva Medical School, Geneva, Switzerland; Department of Basic Neurosciences, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva, University of Geneva Medical Center, Geneva, Switzerland. Electronic address: alexandre.dayer@unige.ch.

Abstract

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.

KEYWORDS:

22q11; Corticogenesis; DGCR2; Neuronal migration; Reelin; Schizophrenia

PMID:
29305086
DOI:
10.1016/j.biopsych.2017.11.015
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