The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis
| Autor: | Alexandre Dayer, Aude Molinard-Chenu |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Risk Cell Adhesion Molecules Neuronal Neurogenesis Mutation Missense Nerve Tissue Proteins Biology Neuronal migration 03 medical and health sciences ddc:616.89 Mice 0302 clinical medicine ddc:590 Cell Movement Pregnancy DiGeorge syndrome Corticogenesis medicine Missense mutation Animals Humans Reelin DGCR2 Gene Biological Psychiatry Exome sequencing Genetics Cerebral Cortex Gene knockdown Extracellular Matrix Proteins Serine Endopeptidases medicine.disease ddc:616.8 22q11 Mice Inbred C57BL Reelin Protein 030104 developmental biology Electroporation HEK293 Cells nervous system Platelet Glycoprotein GPIb-IX Complex biology.protein Schizophrenia Female Haploinsufficiency 030217 neurology & neurosurgery |
| Zdroj: | Biological Psychiatry, Vol. 83, No 8 (2018) pp. 692-706 |
| ISSN: | 1873-2402 0006-3223 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect