Abnormal microenvironmental signals underlie intestinal aganglionosis in Dominant megacolon mutant mice

Raj P. Kapur, Robert Livingston, Barbara Doggett, David A. Sweetser, Joseph R. Siebert, Richard D. Palmiter

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Dominant megacolon (Dom) is a mutation in an uncharacterized murine gene which is associated with intestinal aganglionosis and the focal absence of melanocytes in heterozygous animals. The phenotype of Dom/+ heterozygotes is similar to the lethal spotted and piebald lethal mutations, which are due to defects in endothelin-mediated intercellular signals. In this study, the DβH-nlacZ transgenic marker for enteric neural crest cells is used to study the distribution of enteric neurons and their precursors in Dom/+ mice and embryos. Vagal neural crest-derived cells in wild-type embryos colonize the gut in a cranial-to-caudal progression. In Dom/+ embryos, colonization was retarded from the earliest stages examined (embryonic Day 11.0), including progression through the small intestine. The early onset of this defect contrasts with impaired neural crest colonization associated with the lethal spotted and piebald lethal mutations which manifest only in the large intestine. Analysis of Dom/+ ⇆ +/+ aggregation chimeras indicated that defective colonization is not an autonomous (intrinsic) property of Dom/+ neuroblasts, but like lethal spotted and piebald lethal, the Dominant megacolon mutation directly or indirectly affects microenvironmental signals which influence the migration, proliferation, and/or survival of enteric neural crest cells.

Original languageEnglish (US)
Pages (from-to)360-369
Number of pages10
JournalDevelopmental biology
Volume174
Issue number2
DOIs
StatePublished - Mar 15 1996

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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