Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3

Abstract

The enteric nervous system mediates reflexes independently of the brain and spinal cord and transmits signals bidirectionally between the gut and the brain. Hirschsprung disease and chronic intestinal pseudo-obstruction (CIPO) and pediatric CIPO are examples of congenital defects that impair gastrointestinal motility. In this issue of the JCI, Thuy-Linh Le et al. analyzed eight patients with defects in tissue that arose from the neural crest. The patients carried homozygous or heterozygous variants in ERBB3 or ERBB2, which encode transmembrane epidermal growth factor receptors that bind neuroregulin 1 (NRG1). Notably, the genetic variants resulted in loss of function with decreased expression or aberrant phosphorylation of the ERBB3/ERBB2 receptors. Experiments using mice revealed that Erbb3 and Erbb2 were expressed in enteric neuronal progenitor cells. This study is an outstanding example of descriptive observation that begs for mechanistic exploration to reveal precisely how the NRG1/ERBB3/ERBB2 pathway influences ENS development.

Figure 1. Dysregulation of ERBB2 and ERBB3 signaling as the molecular basis of a diverse array of developmental disorders.

Le et al. (18) described patients with neurocristopathies, developmental disorders arising from the neural crest; the most prominent included congenital aganglionosis of the terminal bowel (HSCR) and CIPO or PIPO. Some individuals had arthrogryposis, possibly due to disordered development of skeletal muscle myotubes. The authors identified variants in ERBB2/ERBB3 genes, which encode transmembrane epidermal growth factor receptors and bind NRG1. ERBB3/ERBB2 was expressed in enteric neuronal progenitor cells, which derive from the neural crest. The loss-of-function ERBB3/ERBB2 variants resulted in reduced expression and altered signaling. The figure was adapted with permission from Rao et al., Hicks et al., and Choi et al. (4, 24, 25).