title: PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling.
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 1919bp 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.
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors: Janice Hiu-Chor
authors: JH
authors: Plani-Lam
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors: Tai-Cheong
authors: TC
authors: Chow
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors: Kam-Leung
authors: KL
authors: Siu
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors: Wing Hin
authors: WH
authors: Chau
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China; Poison Treatment Centre, Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, Hong Kong, China.
authors: Ming-Him James
authors: MH
authors: Ng
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors: Suying
authors: S
authors: Bao
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors: Cheung Toa
authors: CT
authors: Ng
authors: Department of Psychiatry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China; Centre for Genomic Sciences, University of Hong Kong, 5 Sassoon Road, Hong Kong, China.
authors: Pak
authors: P
authors: Sham
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors: Daisy Kwok-Yan
authors: DK
authors: Shum
authors: Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, The University of Western Australia, Crawley, Western Australia, 6009, Australia.
authors: Evan
authors: E
authors: Ingley
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China.
authors: Dong-Yan
authors: DY
authors: Jin
authors: Department of Biochemistry, University of Hong Kong, 21 Sassoon Road, Hong Kong, China. Electronic address: songy@hku.hk.
authors: You-Qiang
authors: YQ
authors: Song
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D020880:Neuregulins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D040641:Quantitative Trait Loci; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486357:NRG3 protein, human; D020880:Neuregulins; C108113:Nrg3 protein, mouse; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; C409985:PTPN21 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C522213:Ptpn21 protein, mouse
keywords: ErbB4; NRG3; Neuritic elongation; PTPN21; Pro-neuronal survival