Neuregulin 1 is involved in enteric nervous system development in zebrafish

Background: Hirschsprung's disease (HD, also known as congenital colon aganglionosis) is a congenital disorder characterized by the absence of intramural ganglion cells in the distal gastrointestinal tract, which results in tonic contraction of the aganglionic gut segment and functional intestinal obstruction. Recent studies have indicated neuregulin 1 (NRG1) as a new candidate gene involved in the development of the enteric nervous system (ENS) in humans. Methods: In our study, we investigated the role of NRG1 in zebrafish ENS development by assessing NRG1 expression patterns during ENS development. Knockdown, overexpression and rescue zebrafish models of NRG1 were created to evaluate differences in phenotype, numbers of enteric neurons, ENS-related factors and nerve fiber arrangements. Results: NRG1 was expressed in zebrafish intestine at both the larval and adult stage. We also found that decreased expression of NRG1 resulted in reductions in enteric neuron number and decreased expression of ENS development markers. Moreover, NRG1-knockdown zebrafish exhibited a disordered arrangement of nerve fibers. Conclusions: Collectively, these results demonstrated that NRG1 expression might play a role in zebrafish ENS development. In addition, by modulating NRG1 expression, we created a model that may be useful for investigating the mechanism underlying HD pathogenesis.