High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes.
High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes.
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DOI：
10.1038/boneres.2014.34
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发表时间：
2014
期刊：
影响因子：
12.7
通讯作者：
Vogel, Peter
中科院分区：
文献类型：
--
作者：
Brommage, Robert;Liu, Jeff;Hansen, Gwenn M.;Kirkpatrick, Laura L.;Potter, David G.;Sands, Arthur T.;Zambrowicz, Brian;Powell, David R.;Vogel, Peter
在体内筛选基因功能是发现新的药物靶点的有效途径。我们提供了3个 762不同的全球基因敲除(KO)小鼠品系的高通量筛选数据，这些小鼠是使用基因陷阱或同源重组技术产生的存活的成年纯合子小鼠。通过14周龄雄性和雌性小鼠的DEXA扫描和16周龄雄性小鼠骨骼的MicroCT分析来测定骨量。对野生型(WT)笼鼠/窝鼠的每个基因KO进行了检测。在另外850个KO品系中观察到了致死性。由于原发HTS易受假阳性结果的影响，因此对具有耐人寻味的HTS骨骼数据的KO系小鼠的额外队列进行了检查。进行了年龄、卵巢切除、组织形态计量学和骨强度研究，并探索了可能的非骨骼表型。这些筛选发现了多个影响骨量的基因：23个先前已报道的基因(Calcr、CEBPB、Crap、Dcstamp、Dkk1、Duoxa2、Enpp1、FGF23、Kiss1/Kiss1r、Kl(Klotho)、LRP5、Mstn、Neo1、Npr2、Ostm1、postn、sFRP4、Slc30a5、Slc39a13、Sost、Sumf1、Src、Wnt10b)、5个新基因(Cldn18、Fam20c、Lrrk1、Sgpl1、Wnt16)、5个具有初步特征的新基因(AGPAT2、Rassf5、Slc10a7、Slc26a7、Slc30a10)和3个未披露的潜在骨质疏松症靶点编码基因。
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/Kiss1r, Kl (Klotho), Lrp5, Mstn, Neo1, Npr2, Ostm1, Postn, Sfrp4, Slc30a5, Slc39a13, Sost, Sumf1, Src, Wnt10b), five novel genes extensively characterized (Cldn18, Fam20c, 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.
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影响因子：
11.8
作者：
Arnold, Michael A.;Kim, Yuri;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
16.2
作者：
Agalliu, Dritan;Takada, Shinji;Jessell, Thomas M.
通讯作者：
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影响因子：
6.2
作者：
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通讯作者：
McKee, Marc D.
影响因子：
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作者：
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通讯作者：
Krumlauf, Robb
影响因子：
7.3
作者：
Bagdanoff, Jeffrey T.;Donoviel, Michael S.;Augeri, David J.
通讯作者：
Augeri, David J.