Heparin-binding epidermal growth factor–like growth factor promotes murine enteric nervous system development and enteric neural crest cell migration

Abstract

Background/PurposeDevelopmental defects of the enteric nervous system lead to a variety of disorders including Hirschprung disease. We have previously shown that heparin-binding epidermal growth factor–like growth factor (HB-EGF) exerts neuroprotective effects on injured neurons. The goals of this study were to assess the role of HB-EGF in enteric nervous system development and to evaluate the effect of HB-EGF on enteric neural crest–derived cell (ENCC) migration in the developing gastrointestinal tract of mice. Materials and MethodsHB-EGF immunohistochemistry was used to examine HB-EGF protein expression in the hindgut of embryonic mice. Gut specimens were stained for PGP9.5 (a neuronal cell marker) to examine the extent of ENCC migration in the intestine at different embryonic stages in HB-EGF knockout (KO) and wild-type (WT) mice. Embryonic gut organ cultures were established to examine the effect of HB-EGF on ENCC migration. ResultsThe expression of HB-EGF was limited to the endodermal epithelium of the hindgut in early gestation, but rapidly involved the hindgut mesenchyme after ENCC migrated into this region. ENCC migration was significantly delayed in HB-EGF KO compared with WT embryos, leading to defects in neural colonization of the distal gut in postnatal HB-EGF KO mice. Addition of HB-EGF to WT embryonic intestine significantly promoted ENCC migration, as demonstrated by a significant increase in the ratio of ENCC migration distance toward the distal hindgut/total colon length (78% ± 4% vs 53% ± 2%, P = .001). ConclusionsDeletion of the HB-EGF gene leads to enteric nervous system developmental defects. HB-EGF stimulates ENCC migration in the gut, supporting a potential role for administration of HB-EGF in the future for the treatment of patients with intestinal neuronal disorders.