Neuregulin 3

The neuregulins are a diverse family of proteins formed through alternative splicing from a single gene; they play crucial roles in regulating the growth and differentiation of epithelial, glial and muscle cells. These groups of proteins also aid cell-cell associations in the breast, heart and skeletal muscles. Four different kinds of neuregulin genes have been identified, namely: NRG1 NRG2 NRG3 and NRG4. While the NRG1 isoforms have been extensively studied, there is little information available about the other genes of the family. NRGs bind to the ERBB3 and ERBB4 tyrosine kinase receptors; they then form homodimers or heterodimers, often consisting of ERBB2, which is thought to function as a co-receptor as it has not been observed to bind any ligand. NRGs bind to the ERBB receptors to promote phosphorylation of specific tyrosine residues on the C-terminal link of the receptor and the interactions of intracellular signaling proteins.

NRGs also play significant roles in developing, maintaining, and repair of the nervous system; this is because NRG1, NRG2 and NRG3 are widely expressed in the central nervous system and also in the olfactory system. Studies have observed that in mice, NRG3 is limited to the developing Central nervous system as well as the adult form; previous studies also highlight the roles of NRG1, ERBB2, and ERBB4 in the development of the heart. Mice deficient in ERBB2, ERBB4, or NRG1 were observed to die at the mid-embryogenesis stage from the termination of myocardial trabeculae development in the ventricle. These results confirm that NRG1 expression in the endocardium is a significant ligand required to activate expression of ERBB2 and ERBB4 in the myocardium.

Function

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.

NRG1, plays critical roles in the development of the embryonic cerebral cortex when it controls migration and sequencing of the cortical cell. 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. The recent discovery of hFBNRG3 (human fetal brain NRG3; DQ857894) which is an alternative cloned isoform of NRG3 from human fetal brain, promotes the survival of oligodendrocyte with the aid of ERBB4/PI3K/AKT1 pathway 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.