Neuregulin 3

Neuregulins are ligands of the ERBB-family receptors, while NRG1 and NRG2 are able to bind and activate both ERBB3 and ERBB4, NRG3 binding stimulates tyrosine phosphorylation, and can only bind to the extracellular domain of the ERBB4 receptor tyrosine kinase but not to the other members of the ERBB family receptors; ERBB2 and ERBB3. Contrary to NRG1, there is limited information on pre-mRNA splicing of the NRG3 gene, together with its transcriptional profile and function in the brain. and also partakes in NRG3-ERBB4 signaling in neurodevelopment and brain functionalities. Even though studies have revealed that NRG1 and NRG3 are paralogues, the EGF domain of NRG3 is only 31% identical to NRG1. The N-terminal domain of NRG3 resembles that of Sensory And Motor Neuron Derived Factor; SMDF because it lacks Ig-like as well as Kringle-like domains that are attributed to many NRG1 isomers. Hydropathy profile studies have shown that NRG3 lacks a hydrophobic N-terminal signal sequence common in secreted proteins, but contains a region of non-polar or uncharged amino acids in position (W66–V91). An amino acid region found in SMDF is similar to this non polar site of NRG3 and has been proposed to act as an internal, uncleaved signal sequence that functions as a translocation agent across the endoplasmic reticulum membrane. == Clinical significance ==

Recent human genetic studies reveals neuregulin 3 gene (NRG3) as a potential risk gene responsible for different kinds of neuro-developmental disorders, resulting to schizophrenia, stunted development, attention deficit related disorders and bipolar disorders when structural and genetic variations occur within the gene Most importantly, variants of the NRG3 gene have been linked to a susceptibility to schizophrenia. An increase in Isoform-specific models of NRG3 involved in schizophrenia have been reported, and observed to have an interaction with rs10748842; a NRG3 risk polymorphism, which indicates that NRG3 transcriptional dysregulation is a molecular risk mechanism. These isoforms have also been linked to Hirschsprung's disease. Schizophrenia Several genes in the NRG-ERBB signaling pathway have been implicated in genetic predisposition to schizophrenia, Neuregulin 3 (NRG3) encodes a protein similar to its paralog NRG1 and both play important roles in the developing nervous system. As observed with other pathologies like autism and schizophrenia, several members of any given protein family have a high chance of association with the same phenotype, individually or together. A recent study of the temporal, diagnostic, and tissue-specific modulation of NRG3 isoform expression in human brain development, employed the use of qRT-PCR; quantitative polymerase chain reaction to quantify 4 classes of NRG3 in human postmortem dorsolateral prefrontal cortex from 286 normal and affected (bipolar or extreme depressive disorder) candidates with age range of 14 weeks to 85 years old. The researches observed that each the 4 isoform class (I-IV) of NRG3 showed unique expression trajectories across human neopallium development and aging. • NRG3 class I was increased in bipolar and major depressive disorder, in agreement with observations in schizophrenia. • NRG3 class II was increased in bipolar disorder, and class III was increased in major depression cases. • NRG3 class I, II and IV were actively involved in the developmental stages, • The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. == References ==