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首页> 外文期刊>Development >Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis.
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Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis.

机译：表达显性阴性Ret突变表型的人类Hirschsprung疾病的小鼠，描绘了Ret在精子发生中的直接作用。

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摘要

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.
机译：Ret受体酪氨酸激酶介导神经胶质细胞系神经营养因子（GDNF）家族配体（GFLs）的生理信号，对于小鼠的出生后生存至关重要。它与许多人类疾病和发育异常有关。在这里，我们描述了我们对表达Ret突变体（RetDN）的小鼠的分析，该突变体具有抑制野生型Ret活性（包括其AKT激活）的激酶活性。所有RetDN / +小鼠均在1个月大时死亡，并在人类中引起远端肠神经节病，使人联想到Hirschsprung病（HSCR）。 RetDN / +近端小肠也有严重的神经节节减低和神经纤维密度降低，提示术后HSCR患者持续胃动力不良的潜在机制。与Ret-null小鼠的副交感神经和交感神经系统异常不同，RetDN / +小鼠仅在副交感神经系统中具有缺陷。 RetDN / +小鼠中有一小部分患有肾发育不全，其余的小鼠肾脏发育不良，并且在出生后出现肾小管囊性异常。睾丸的产后分析显示，生殖细胞数量减少，曲细精管退化，成熟停滞和细胞凋亡，表明Ret在早期精子发生中起关键作用。

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