Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival

Abstract

Neuregulins are a family of genes involved in key aspects of neural biology. Neuregulins 1, 2 and 3 (NRG1, NRG2 and NRG3) are expressed in the mammalian nervous system. It is well established that NRG1, with fifteen different splicing forms, is central for brain development and function. However, the biological relevance of NRG2 and NRG3 remains elusive. Here, we report the identification of a new isoform of NRG3 that is specifically expressed in the human embryonic central nervous system. Sequence alignment with the human genome suggests that this transcript is produced by alternative promoter usage. The encoded polypeptide is a type-I-glycosylated plasma membrane protein, which is shed into the extracellular space where it activates erbB4, a pivotal receptor for brain development. In addition, we show that the protein has a signal sequence that is cleaved after membrane insertion. Proteasome inhibition with Lactacystin enhances the expression of the protein, whereas impairment of ubiquitylation in the conditional mutant cell line ts20 protects the protein from degradation. These observations imply that the ubiquitin/proteasome pathway regulates biogenesis of the protein. We also show that recombinant neuregulin 3 acts as an oligodendrocyte survival factor by activating the phosphoinositide 3-kinase signalling pathway. Therefore, we report a new post-translationally regulated isoform of neuregulin 3 expressed in the developing human central nervous system with a role in oligodendrocyte survival.

Common genetic variation in Neuregulin 3 ( NRG3 ) influences risk for schizophrenia and impacts NRG3 expression in human brain

“…2, transcript 4). Our transcript differs from that of Carteron et al (15) because of splicing of exon 11 (amino acids IEVRK-TISHLPIQLWCVERPLDLK; Fig. 2).…”

“…Association to two of these SNPs (rs10883866 and rs6584400) and delusional traits in schizophrenia has recently been confirmed (5). The noncoding polymorphisms reside in a 5′-conserved block of linkage disequilibrium (LD) proximal to an alternative promoter and transcription start site for hFBNRG3 (4,15). The physical location of the polymorphisms suggests that they may mediate disease risk via transcriptional regulation of developmentally expressed isoforms containing the proximal 5′ exon of hFBNRG3.…”

“…In contrast to NRG1 (13,14), little is known about pre-mRNA splicing of the NRG3 gene, its transcriptional profile, or function in human brain. The recent identification of hFBNRG3 (human fetal brain NRG3; DQ857894), an alternative isoform of NRG3 cloned from human fetal brain that promotes oligodendrocyte survival via the ErbB4/PI3K/AKT1 pathway (15), implicates NRG3-ErbB4 signaling in neurodevelopment and adult brain function.…”

Characterization of the cell membrane-associated products of the Neuregulin 4 gene

“…It has also been reported that the expression of a splice variant of NRG3 (hFBNRG3) which is found in human foetal brain is enhanced in the presence of proteosome inhibitors, and the authors suggest that proteosomal degradation of this protein may be indirectly mediated by ubiquitination (Carteron et al, 2006). Both NRG4 isoforms contain lysine residues (NRG4A1/A2 K14, K57 and additionally NRG4A1 K83), which might be targets for ubiquitination (although only K83 is predicted to be intracellular).…”

“…NRG2 is also alternatively spliced to produce a and b variants (Yamada et al, 2000), and recently isoforms of NRG3 have been described (Carteron et al, 2006). There have previously been no reports of NRG4 splice variants.…”