Mechanisms of Neuregulin Action

Abstract

Neuregulin 1 (Nrg1) and ErbB receptor tyrosine kinase signalling is essential for the formation and proper functioning of multiple organ systems and inappropriate Nrg1/ErbB signalling severely compromises health, contributing to such diverse pathologies as cancer and neuropsychiatric disorders. Numerous genetic modelling studies in mice demonstrate that Nrg1 signalling is important in the development of normal neuronal connectivity. Recent studies have identified novel signalling mechanisms and revealed unexpected roles of Nrg1 isoforms in both the developing and adult nervous system. Of particular interest to this discussion are findings linking deficits in Nrg1-ErbB4 signalling to perturbations of synaptic transmission, myelination, and the survival of particular sets of neurons and glia.

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…In contrast, these same Nrg1 models show deficits in evoked gamma oscillations induced by whisker stimulation (Barz et al 2014), auditory cues -albeit all Nrg1 mutant mice are known to have auditory abnormalities (Jin et al 2011;Kato et al 2015;Stankovic et al 2004;Tang et al 2015) -and the psychotomimetic, ketamine (Long et al 2015) whilst addition of Nrg1 in wild-type mice has been shown to enhance kainic-acid evoked gamma oscillations in prefrontal cortex (Hou et al 2014) and hippocampus (Fisahn et al 2009), the former in vivo and the latter in vitro. One study also suggests that excess Nrg1 may lead to similar impairments, as peak frequency, but not amplitude, of gamma oscillations were reduced in type I Nrg1 over-expressing mice (Deakin et al 2012), which also supports the inverted "U" model of Nrg1 function (Agarwal et al 2014;Law 2014;Talmage 2008). Gamma oscillations are linked to cognitive performance in humans (Engel et al 2015;Heermann et al 2011;Jensen et al 2007) and mice with abnormal Nrg1 expression which have the aforementioned deficits in evoked gamma oscillations, also have cognitive deficits (Agarwal et al 2014;Barz et al 2014;Chen et al 2008;Chesworth et al 2012;Duffy et al 2010;Yin et al 2013).…”

CD74–NRG1 Fusions in Lung Adenocarcinoma

“…The NRG1 isoform present in our fusion transcript belongs to the type III and carries the EGFlike domain type β, which has higher affi nity to the receptors than the α-type ( 12 ). NRG1 type III expression is mostly limited to neurons and is the only isoform displaying this degree of tissue-specifi c expression ( 13 ). Only the sample carrying the CD74-NRG1 fusion exhibited high expression of the NRG1 III-β3 isoform [74 fragments per kilobase per million reads (FPKM); Fig.…”

In silico analysis of neuregulin 1 evolution in vertebrates

“…N-terminal coding regions of type I (lizard) and type II [chicken, lizard and frog (X. tropicalis)] NRG1s cannot be identified (UI) from the limited sequence data (lizard scaffold sequence) or ambiguous regions (horse, chicken and frog databases). Although type IV NRG1 was considered to be restricted to primates [17], the N-CDS can be identified in horse and cow databases. The spacer of NRG1 encoded by CDS 51a and CDS 51b cannot be identified in non-mammalian genes, and CDSs for the b-and c-tails appear to be non-existent except for frog nrg1.…”

“…The N-terminal domain of the type III isoform SMDF (sensory and motor neuron-derived factor) embeds a unique cysteine-rich TM domain [26] among all types of NRG1s as well the cytosolic N-termini to form homodimers via disulfide bridges. The alignments in Supplementary Figure S6 (see http://www.bioscirep.org/bsr/030/bsr0300267add.htm) show the conservations [17] in all ten vertebrate sequences as well a conserved myristylated motif in most of the sequences except frog and Danio. In addition, non-mammalian NRG1s do not contain the spacer (CDS 51a -CDS 51b ; see Supplementary Table S1 and Supplementary Figure S1); however, the cDNA clone of another amphibian X. laevis nrg1 [27] has been demonstrated to encode a longer spacer.…”