Neuregulin‐1 is essential for nerve plexus formation during cardiac maturation

Abstract

The Neuregulin‐1 (Nrg1)/ErbB pathway plays multiple, critical roles in early cardiac and nervous system development and has been implicated in both heart and nerve repair processes. However, the early embryonic lethality of mouse Nrg1 mutants precludes an analysis of Nrg1's function in later cardiac development and homeostasis. In this study, we generated a novel nrg1 null allele targeting all known isoforms of nrg1 in zebrafish and examined cardiac structural and functional parameters throughout development. We found that zebrafish nrg1 mutants instead survived until young adult stages when they exhibited reduced survivorship. This coincided with structural and functional defects in the developing juvenile and young adult hearts, as demonstrated by reduced intracardiac myocardial density, cardiomyocyte cell number, swimming performance and dysregulated heartbeat. Interestingly, nrg1 mutant hearts were missing long axons on the ventricle surface by standard length (SL) 5 mm, which preceded juvenile and adult cardiac defects. Given that the autonomic nervous system normally exerts fine control of cardiac output through this nerve plexus, these data suggest that Nrg1 may play a critical role in establishing the cardiac nerve plexus such that inadequate innervation leads to deficits in cardiac maturation, function and survival.

Neuregulins in Neurodegenerative Diseases

“…The results of a growing number of studies suggest that NRG1 regulates cell maintenance, differentiation, proliferation, migration, and survival or apoptosis in both neuronal and nonneuronal cell types (Mei and Xiong, 2008). Research on NRGs and their corresponding receptors in both invertebrate and vertebrate models, including Drosophila (Hidalgo et al, 2001), zebrafish (Brown et al, 2017), mouse (Kato et al, 2009), rat (Zhao et al, 2015) and even non-human primate rhesus monkey (Zhao, 2013b), have shown their complex involvement in the development of the nervous system and related diseases.…”

From Mice to Mainframes: Experimental Models for Investigation of the Intracardiac Nervous System

“…Despite the advantages of the zebrafish for developmental studies, there is a paucity of reports describing IcNS anatomy and the mechanisms of its development in embryonic zebrafish [95]. While the presence of parasympathetic (e.g., M 2 muscarinic receptors) and sympathetic (e.g., β-adrenergic receptors) receptors in the larval zebrafish have been established [96,97], and their functional relevance has been substantiated by pharmacological studies [98], specific details of the structure and function of this system in development remain to be described.…”

The Potential of Gamma Secretase as a Therapeutic Target for Cardiac Diseases

“…The NRG1-ErbB2/4 complex was also shown to upregulate the differentiation and speciation of cardiac progenitor cells into cardiomyocytes [100]. Studies using NRG1 mutated zebrafish models showed that the defects led to a reduction in the number of cardiomyocytes, a decrease in the density of the intracardiac myocardium, as well as improper regulation of the heartbeat [101]. It was established that NRG1 plays a vital role in the formation of the cardiac nerve plexus, thereby exerting an effect on cardiac development [101].…”

“…Studies using NRG1 mutated zebrafish models showed that the defects led to a reduction in the number of cardiomyocytes, a decrease in the density of the intracardiac myocardium, as well as improper regulation of the heartbeat [101]. It was established that NRG1 plays a vital role in the formation of the cardiac nerve plexus, thereby exerting an effect on cardiac development [101]. The NRG1-ErbB2/4 also mediates the conversion of fetal cardiac cells into pacemaker cells [99].…”