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

Janice Plani-Lam, T. Chow, K. Siu, W. Chau, M.H.J. Ng, S. Bao, C. Ng, P. Sham, D. Shum, Evan Ingley, D. Jin, Y. Song

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

© 2015 Elsevier Ltd. All rights reserved. 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.
Original languageEnglish
Pages (from-to)53-62
JournalInternational Journal of Biochemistry and Cell Biology
Volume61
DOIs
Publication statusPublished - 2015

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