期刊
DEVELOPMENT
卷 131, 期 21, 页码 5503-5513出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.01421
关键词
Ret; GDNF; Hirschsprung disease; spermatogenesis
资金
- NCI NIH HHS [T32CA09547-17] Funding Source: Medline
- NIA NIH HHS [AG13730] Funding Source: Medline
- NICHD NIH HHS [L40 HD045452-01, L40 HD045452-02, K08 HD047396, K08 HD047396-01, L40 HD045452] Funding Source: Medline
- NINDS NIH HHS [NS39358] Funding Source: Medline
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 wildtype Ret activity, including its activation of AKT. All Ret(DN/+), mice died by 1 month of age and had distal intestinal aganglionosis reminiscent of Hirschsprung disease (HSCR) in humans. The Ret(DN/+), 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 Ret(DN/+), mice only had defects in the parasympathetic nervous system. A small proportion of Ret(DN/+), 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.
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