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PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling

Plani-Lam, J.H.C., Chow, T-C, Siu, K-L, Chau, W.H., Ng, M-H.J., Bao, S., Ng, C-T, Sham, P., Shum, D.K-Y, Ingley, E.ORCID: 0000-0002-8112-9134, Jin, D-Y and Song, Y-Q (2015) PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling. The International Journal of Biochemistry & Cell Biology, 61 . pp. 53-62.

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Although expression quantitative trait locus, eQTL, serves as an explicit indicator of gene-gene associations, challenges remain to disentangle the mechanisms by which genetic variations alter gene expression. Here we combined eQTL and molecular analyses to identify an association between two seemingly non-associated genes in brain expression data from BXD inbred mice, namely Ptpn21 and Nrg3. Using biotinylated receptor tracking and immunoprecipitation analyses, we determined that PTPN21 de-phosphorylates the upstream receptor tyrosine kinase ErbB4 leading to the up-regulation of its downstream signaling. Conversely, kinase-dead ErbB4 (K751R) or phosphatase-dead PTPN21 (C1108S) mutants impede PTPN21-dependent signaling. Furthermore, PTPN21 also induced Elk-1 activation in embryonic cortical neurons and a novel Elk-1 binding motif was identified in a region located 1919 bp upstream of the NRG3 initiation codon. This enables PTPN21 to promote NRG3 expression through Elk-1, which provides a biochemical mechanism for the PTPN21-NRG3 association identified by eQTL. Biologically, PTPN21 positively influences cortical neuronal survival and, similar to Elk-1, it also enhances neuritic length. Our combined approaches show for the first time, a link between NRG3 and PTPN21 within a signaling cascade. This may explain why these two seemingly unrelated genes have previously been identified as risk genes for schizophrenia.

Item Type: Journal Article
Publisher: Elsevier Limited
Copyright: © 2015 Elsevier Ltd.
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