Congenic mice provide in vivo evidence for a genetic locus that modulates serum insulin-like growth factor-I and bone acquisition
Congenic mice provide in vivo evidence for a genetic locus that modulates serum insulin-like growth factor-I and bone acquisition
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DOI：
10.1210/en.2006-0277
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发表时间：
2006-08-01
期刊：
影响因子：
4.8
通讯作者：
Rosen, C. J.
中科院分区：
文献类型：
--
作者：
Delahunty, K. M.;Shultz, K. L.;Rosen, C. J.
我们通过对C57 BL/6 J（B6）x C3 H/HeJ（C3 H）杂交小鼠进行全基因组扫描，确定了决定血清IGF-I遗传变异的数量性状位点（QTL）。一个QTL（Igf 1 s2），在小鼠染色体10（Chr 10），产生了15%的增加血清IGF-I在B6 C3 F2小鼠携带c3等位基因在该位置。我们构建了一个同类小鼠，B6。C3 H-10（10 T），通过将来自该57-Mb区域的c3等位基因回交到B6中10代。与B6相比，10 T小鼠在16 wk时具有更高的血清和骨骼IGF-I、更大的骨小梁体积分数、更多的骨小梁和更多的破骨细胞（P < 0.05）。进一步回交10 T产生的巢式同源亚系允许重组，并产生4个较小的亚系，其在16周时血清IGF-I显著增加（i. e. 10-4、10-7、10-10和10-13），与B6（P < 0.0003）相比，以及三个较小的亚系，其在IGF-I与年龄和性别匹配的B6小鼠中没有显示差异。与10 T一样，10-4巢式亚系在16 wk时具有更高的股骨矿物质（P < 0.0001）和更大的骨小梁连接密度，骨小梁显著多于B6（P < 0.01）。因此，通过综合表型分析，我们能够将QTL缩小到包含约148个基因的18.3 Mb区域，包括Igf 1和Elk-3（ETS结构域蛋白）。Igf 1 s2 QTL的等位基因差异产生了一种表型，其特征在于血清IGF-I增加和骨密度峰值增大。同类小鼠建立了循环IGF-I和骨获取的共享遗传决定因素的概念证据。
We identified quantitative trait loci (QTL) that determined the genetic variance in serum IGF-I through genome-wide scanning of mice derived from C57BL/6J(B6) x C3H/HeJ(C3H) intercrosses. One QTL (Igf1s2), on mouse chromosome 10 (Chr10), produces a 15% increase in serum IGF-I in B6C3 F2 mice carrying c3 alleles at that position. We constructed a congenic mouse, B6. C3H-10 (10T), by backcrossing c3 alleles from this 57-Mb region into B6 for 10 generations. 10T mice have higher serum and skeletal IGF-I, greater trabecular bone volume fraction, more trabeculae, and a higher number of osteoclasts at 16 wk, compared with B6 (P < 0.05). Nested congenic sublines generated from further backcrossing of 10T allowed for recombination and produced four smaller sublines with significantly increased serum IGF-I at 16 wk (i. e. 10-4, 10-7, 10-10, and 10-13), compared with B6 (P < 0.0003), and three smaller sublines that showed no differences in IGF-I vs. age- and gender-matched B6 mice. Like 10T, the 10-4 nested sublines at 16 wk had higher femoral mineral (P < 0.0001) and greater trabecular connectivity density with significantly more trabeculae than B6 (P < 0.01). Thus, by comprehensive phenotyping, we were able to narrow the QTL to an 18.3-Mb region containing approximately 148 genes, including Igf1 and Elk-3(ETS domain protein). Allelic differences in the Igf1s2 QTL produce a phenotype characterized by increased serum IGF-I and greater peak bone density. Congenic mice establish proof of concept of shared genetic determinants for both circulating IGF-I and bone acquisition.