A novel dwarfism with gonadal dysfunction due to loss-of-function allele of the collagen receptor gene, Ddr2, in the mouse
A novel dwarfism with gonadal dysfunction due to loss-of-function allele of the collagen receptor gene, Ddr2, in the mouse
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DOI：
10.1210/me.2007-0310
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发表时间：
2008-08-01
影响因子：
--
通讯作者：
Naggert, Juergen K.
中科院分区：
文献类型：
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作者：
Kano, Kiyoshi;de Evsikova, C. Marin;Naggert, Juergen K.
Smallie（Slie）是一种自发的常染色体隐性突变，可导致小鼠侏儒和不育.本研究的目的是确定和表征其表型的潜在分子遗传基础。将slie基因定位在第1染色体上，精细结构定位将slie等位基因缩小到遗传标记D1Mit36和Mpz之间的2Mb内。为了查明潜在的突变，使用定量真实的时间PCR来测量驻留在该区域内的基因的相对表达水平。其中一个基因，Ddr2，编码盘状结构域受体2（DDR2）的表达，在Slie纯合子小鼠中缺失。基因组测序分析检测到一个150 kb的缺失延伸到Ddr2基因转录本。详细的表型分析表明，性腺功能失调是slie小鼠不育的基础，因为所有雌性小鼠均无排卵，大多数成年雄性小鼠缺乏精子发生。青春期前slie小鼠的脑垂体比野生型小鼠小。垂体和下丘脑激素的基础水平和基因表达，以及下丘脑释放激素的基因表达，在slie和野生型小鼠之间没有显著差异。尽管肝脏中的IGF-1 mRNA表达较低，但Slie小鼠的循环IGF-1水平没有差异。外源性促性腺激素给药后，雄性和雌性成年slie小鼠分泌的类固醇激素水平与成年野生型小鼠相比变钝，但与青春期前野生型小鼠相似.综上所述，我们的结果表明，在slie小鼠中，由于激素应答途径中的外周缺陷，DDR2的缺乏导致生长迟缓和性腺功能障碍。
Smallie (slie), a spontaneous, autosomal- recessive mutation causes dwarfing and infertility in mice. The purpose of this study was to determine and characterize the underlying molecular genetic basis for its phenotype. The slie locus was mapped to chromosome 1, and fine- structure mapping narrowed the slie allele within 2 Mb between genetic markers D1Mit36 and Mpz. To pinpoint the underlying mutation quantitative real- time PCR was used to measure the relative expression levels for the genes residing within this region. Expression of one gene, Ddr2, which encodes discoidin domain receptor 2 (DDR2), was absent in slie homozygote mice. Genomic sequencing analysis detected a 150-kb deletion that extended into the Ddr2 gene transcript. Detailed phenotype analysis revealed that gonadal dysregulation underlies infertility in slie mice because all females were anovulatory and most adult males lacked spermatogenesis. The pituitary gland of prepubertal slie mice was smaller than in wild- type mice. The basal levels and gene expression for pituitary and hypothalamic hormones, and gene expression for hypothalamic- releasing hormones, were not significantly different between slie and wild- type mice. Circulating levels of IGF-1 did not differ in slie mice despite lower Igf-1 mRNA expression in the liver. After exogenous gonadotropin administration, the levels of secreted steroid hormones in both male and female adult slie mice were blunted compared to adult wild- type, but was similar to prepubertal wild- type mice. Taken together, our results indicate that the absence of DDR2 leads to growth retardation and gonadal dysfunction due to peripheral defects in hormonal- responsive pathways in slie mice.