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First published online 6 October 2004
doi: 10.1242/dev.01421
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1 Department of Pathology and Immunology, Washington University School of
Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
2 Department of Urologic Surgery, Washington University School of Medicine, 660
South Euclid Avenue, St Louis, MO 63110, USA
3 Department of Molecular Biology and Pharmacology, Washington University School
of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
4 Department of Pediatrics, Washington University School of Medicine, 660 South
Euclid Avenue, St Louis, MO 63110, USA
* Author for correspondence (e-mail: jeff{at}pathbox.wustl.edu)
Accepted 25 August 2004
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.
Key words: Ret, GDNF, Hirschsprung disease, Spermatogenesis
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