Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene
Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene
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DOI：
10.1038/ng0497-397
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发表时间：
1997-04-01
期刊：
影响因子：
30.8
通讯作者：
Kirsch, IR
中科院分区：
文献类型：
--
作者：
Good, DJ;Porter, FD;Kirsch, IR
碱性螺旋-环-螺旋（bHLH）基因家族包括参与生长和发育的许多方面的转录因子。我们先前已经描述了两种bHLH转录因子，Nhlh 1和Nhlh 2（最初命名为NSCL 1和NSCL 2）（1-3）。Nhlh 1和Nhlh 2的核苷酸和预测的蛋白质序列在其bHLH结构域内是同源的，其中仅存在三个保守氨基酸差异（2，3）。在小鼠胚胎发生过程中，Nhlh 1和Nhlh 2在发育中的神经系统中具有重叠但不同的表达模式（1，2）。为了提高我们对这些基因在神经发生过程中的作用的理解，我们已经产生了含有两种基因的靶向缺失的小鼠，并在这里描述了我们对Nhlh 2的结果。Nhlh 2的缺失导致小鼠下丘脑-垂体轴的破坏。雄性Nhlh 2-/-小鼠是小阴茎、性腺功能减退和不育的，具有循环促性腺激素的改变、精子发生缺陷和本能雄性性行为的丧失。单独饲养的雌性Nhlh 2-/-小鼠是性腺功能减退的，但是当在雄性存在下饲养时，它们的卵巢和子宫发育正常并且它们是可育的。男性和女性纯合子都表现出进行性成人型肥胖。Nhlh 2在下丘脑腹内侧和外侧、Rathke囊和成人垂体的前叶中表达。我们的研究结果支持Nhlh 2在青春期的开始和体重代谢的调节中的作用。
The family of basic helix-loop-helix (bHLH) genes comprises transcription factors involved in many aspects of growth and development. We have previously described two bHLH transcription factors, Nhlh1 and Nhlh2 (originally named NSCL1 and NSCL2)(1-3). The nucleotide and predicted protein sequences of Nhlh1 and Nhlh2 are homologous within their bHLH domain where there are only three conservative amino acid differences(2,3). During murine embryogenesis, Nhlh1 and Nhlh2 share an overlapping but distinct pattern of expression in the developing nervous system(1,2). To improve our understanding of the role of these genes during neurogenesis, we have generated mice containing targeted deletions of both genes and here describe our results for Nhlh2. Loss of Nhlh2 results in a disruption of the hypothalamic-pituitary axis in mice. Male Nhlh2-/- mice are microphallic, hypogonadal and infertile with alterations in circulating gonadotropins, a defect spermatogenesis and a loss of instinctual male sexual behaviour. Female Nhlh2-/- mice reared alone are hypogonadal, but when reared in the presence of males, their ovaries and uteri develop normally and they are fertile. Both male and female homozygotes exhibit progressive adult-onset obesity. Nhlh2 is expressed in the ventral-medial and lateral hypothalamus, Rathke's pouch and in the anterior lobe of the adult pituitary. Our results support a role for Nhlh2 in the onset of puberty and the regulation of body weight metabolism.