High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes

查看全文 作　　者：Robert [1]Brommage;Jeff [1]Liu;Gwenn M [1]Hansen;Laura L [1]Kirkpatrick;David G [1]Potter;Arthur T [1]Ss;Brian [1]Zambrowicz;David R [1]Powell;Peter [1]Vogel

机构地区：[1]Lexicon Pharmaceuticals, The Woodlands, TX, USA

出　　处：《Bone Research》索引2014年第2卷第3期,共30页

摘　　要：Screening gene function in vivo is a powerful approach to discover novel drug targets. We present high-throughput screening(HTS) data for 3 762 distinct global gene knockout(KO) mouse lines with viable adult homozygous mice generated using either gene-trap or homologous recombination technologies. Bone mass was determined from DEXA scans of male and female mice at 14 weeks of age and by microCT analyses of bones from male mice at 16 weeks of age. Wild-type(WT) cagemates/littermates were examined for each gene KO. Lethality was observed in an additional 850 KO lines. Since primary HTS are susceptible to false positive findings, additional cohorts of mice from KO lines with intriguing HTS bone data were examined. Aging,ovariectomy, histomorphometry and bone strength studies were performed and possible non-skeletal phenotypes were explored. Together, these screens identified multiple genes affecting bone mass: 23 previously reported genes(Calcr, Cebpb, Crtap, Dcstamp, Dkk1, Duoxa2, Enpp1, Fgf23, Kiss1/Kiss1 r, Kl(Klotho),Lrp5, Mstn, Neo1, Npr2, Ostm1, Postn, Sfrp4, Slc30a5, Slc39a13, Sost, Sumf1, Src, Wnt10b), five novel genes extensively characterized(Cldn18, Fam20 c, Lrrk1, Sgpl1, Wnt16), five novel genes with preliminary characterization(Agpat2, Rassf5, Slc10a7, Slc26a7, Slc30a10) and three novel undisclosed genes coding for potential osteoporosis drug targets. 关键词：高通量筛选基因敲除雌性小鼠表型骨架标识 KLOTHO 雄性小鼠

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High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes

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