Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis

Development. 2004 Nov;131(21):5503-13. doi: 10.1242/dev.01421. Epub 2004 Oct 6.


The Ret receptor tyrosine kinase mediates physiological signals of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and is essential for postnatal survival in mice. It is implicated in a number of human diseases and developmental abnormalities. Here, we describe our analyses of mice expressing a Ret mutant (RetDN) with diminished kinase activity that inhibits wild-type Ret activity, including its activation of AKT. All RetDN/+ mice died by 1 month of age and had distal intestinal aganglionosis reminiscent of Hirschsprung disease (HSCR) in humans. The RetDN/+ proximal small intestine also had severe hypoganglionosis and reduction in nerve fiber density, suggesting a potential mechanism for the continued gastric dysmotility in postsurgical HSCR patients. Unlike Ret-null mice, which have abnormalities in the parasympathetic and sympathetic nervous systems, the RetDN/+ mice only had defects in the parasympathetic nervous system. A small proportion of RetDN/+ mice had renal agenesis, and the remainder had hypoplastic kidneys and developed tubulocystic abnormalities postnatally. Postnatal analyses of the testes revealed a decreased number of germ cells, degenerating seminiferous tubules, maturation arrest and apoptosis, indicating a crucial role for Ret in early spermatogenesis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Gene Expression Regulation, Developmental
  • Genes, Dominant / genetics*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Hirschsprung Disease / genetics*
  • Hirschsprung Disease / pathology
  • Humans
  • Kidney / abnormalities
  • Kidney / growth & development
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation / genetics*
  • Nervous System / cytology
  • Nervous System / growth & development
  • Nervous System / metabolism
  • Nervous System / pathology
  • Neurons / cytology
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphotransferases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Spermatogenesis* / genetics
  • Survival Rate


  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Proto-Oncogene Proteins
  • Phosphotransferases
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, mouse