Reduced endothelin converting enzyme-1 and endothelin-3 mRNA in the developing bowel of male mice may increase expressivity and penetrance of Hirschsprung disease-like distal intestinal aganglionosis

Dev Dyn. 2007 Jan;236(1):106-17. doi: 10.1002/dvdy.21028.


Hirschsprung disease (distal intestinal aganglionosis, HSCR) is a multigenic disorder with incomplete penetrance, variable expressivity, and a strong male gender bias. Recent studies demonstrated that these genetic patterns arise because gene interactions determine whether enteric nervous system (ENS) precursors successfully proliferate and migrate into the distal bowel. We now demonstrate that male gender bias in the extent of distal intestinal aganglionosis occurs in mice with Ret dominant-negative mutations (RetDN) that mimic human HSCR. We hypothesized that male gender bias could result from reduced expression of a gene already known to be essential for ENS development. Using quantitative real-time polymerase chain reaction (PCR) we demonstrated reduced levels of endothelin converting enzyme-1 and endothelin-3 mRNA in the male mouse bowel at the time that ENS precursors migrate into the colon. Other HSCR-associated genes are expressed at comparable levels in male and female mice. Testosterone and Mullerian inhibiting substance had no deleterious effect on ENS precursor development, but adding EDN3 peptide to E11.5 male RetDN heterozygous mouse gut explants in organ culture significantly increased the rate of ENS precursor migration through the bowel.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Mullerian Hormone
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Cell Movement
  • Endothelin-3 / genetics
  • Endothelin-3 / metabolism*
  • Endothelin-Converting Enzymes
  • Enteric Nervous System / embryology*
  • Enteric Nervous System / metabolism
  • Female
  • Ganglia, Autonomic / metabolism
  • Glycoproteins / metabolism
  • Hirschsprung Disease / embryology*
  • Hirschsprung Disease / genetics
  • Hirschsprung Disease / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / innervation*
  • Male
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Morphogenesis
  • Mutation
  • Penetrance
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism
  • RNA, Messenger / metabolism
  • Testicular Hormones / metabolism
  • Testosterone / metabolism


  • Endothelin-3
  • Glycoproteins
  • RNA, Messenger
  • Testicular Hormones
  • Testosterone
  • Anti-Mullerian Hormone
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse
  • Aspartic Acid Endopeptidases
  • Metalloendopeptidases
  • ECE1 protein, human
  • Ece1 protein, mouse
  • Endothelin-Converting Enzymes