Journal article
PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling
The International Journal of Biochemistry & Cell Biology, Vol.61, pp.53-62
2015
Abstract
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.
Details
- Title
- PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling
- Authors/Creators
- J.H.C. Plani-Lam (Author/Creator)T-C Chow (Author/Creator)K-L Siu (Author/Creator)W.H. Chau (Author/Creator)M-H.J. Ng (Author/Creator)S. Bao (Author/Creator)C-T Ng (Author/Creator)P. Sham (Author/Creator)D.K-Y Shum (Author/Creator)E. Ingley (Author/Creator)D-Y Jin (Author/Creator)Y-Q Song (Author/Creator)
- Publication Details
- The International Journal of Biochemistry & Cell Biology, Vol.61, pp.53-62
- Publisher
- Elsevier Limited
- Identifiers
- 991005544319807891
- Copyright
- © 2015 Elsevier Ltd.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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