4.5 Article

Schizophrenia risk candidate EGR3 is a novel transcriptional regulator of RELN and regulates neurite outgrowth via the Reelin signal pathway in vitro

期刊

JOURNAL OF NEUROCHEMISTRY
卷 157, 期 6, 页码 1745-1758

出版社

WILEY
DOI: 10.1111/jnc.15225

关键词

EGR3; neurite outgrowth; Reelin signaling pathway; RELN; schizophrenia

资金

  1. National Natural Science Foundation of China [81301151, 31371298]
  2. Natural Science Basic Research Plan in Shaanxi Province of China [2019JM-098]
  3. Fundamental Research Funds for the Central Universities [SXPT012020016]
  4. Scientific Research Funds of Xi'an No.3 Hospital [SYF2020003]

向作者/读者索取更多资源

This study demonstrates that EGR3 regulates neurite outgrowth via the Reelin signaling pathway, is positively correlated with schizophrenia, and may provide a new understanding of the molecular mechanisms of the disorder.
Schizophrenia is a severe psychiatric disorder with a strong hereditary component that affects approximately 1% of the world's population. The disease is most likely caused by the altered expression of a number of genes that function at the level of biological pathways or gene networks. Transcription factors (TF) are indispensable regulators of gene expression. EGR3 is a TF associated with schizophrenia. In the current study, DNA microarray and ingenuity pathway analyses (IPA) demonstrated that EGR3 regulates Reelin signaling pathway in SH-SY5Y cells. ChIP and luciferase reporter studies confirmed that EGR3 directly binds to the promoter region of RELN thereby activating RELN expression. The expression of both EGR3 and RELN was decreased during neuronal differentiation induced by retinoic acid (RA) in SH-SY5Y cells, and EGR3 over-expression reduced neurite outgrowth which could be partially reversed by the knockdown of RELN. The expression levels of EGR3 and RELN in peripheral blood of subjects with schizophrenia were found to be down-regulated (compared with healthy controls), and were positively correlated. Furthermore, data mining from public databases revealed that the expression levels of EGR3 and RELN were presented a positive correlation in post-mortem brain tissue of subjects with schizophrenia. Taken together, this study suggests that EGR3 is a novel TF of the RELN gene and regulates neurite outgrowth via the Reelin signaling pathway. Our findings contribute to the understanding of the regulatory role of EGR3 in the pathophysiology and molecular mechanisms of schizophrenia, and potentially to the development of new therapies and diagnostic biomarkers for the disorder.

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