A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression.
A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression.
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DOI：
10.1002/dvg.22784
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发表时间：
2014-07
期刊：
影响因子：
1.5
通讯作者：
Apte, Suneel S.
中科院分区：
文献类型：
--
作者：
Dubail, Johanne;Aramaki-Hattori, Noriko;Bader, Hannah L.;Nelson, Courtney M.;Katebi, Negin;Matuska, Brittany;Olsen, Bjorn R.;Apte, Suneel S.
关键词：
ADAMTS9是一个具有多种功能的分泌金属蛋白酶大家族中最保守的成员。Adamts9缺失的小鼠在原肠胚形成前死亡，排除了其在胚胎发生、成年小鼠或疾病模型中后期作用的研究。因此，我们产生了一个固定的Adamts9等位基因，以绕过胚胎致死性。在这个突变体中，单向的loxP位点位于外显子5到8的侧面，编码催化结构域，包括蛋白酶活性位点。纯合子的小鼠是活的，没有明显的表型，并且是可育的。相反，通过Cre-lox重组产生的带有柔边等位基因的种系缺失纯合的小鼠不能在原肠胚形成后存活。如前所述，缺失的Adamts9与突变的Adamts20的半合子性导致腭裂和严重的白斑。先前，Adamts9单倍性不足与Adamts20或Adamts5无合子性联合表明在数字间网络回归中起合作作用，但Adamts9单独缺失的结果尚不清楚。在这里，使用Prx1-Cre小鼠在肢体中胚层有条件地删除Adamts9。与其他ADAMTS单敲除不同，肢体特异性Adamts9缺失导致100%外显率的软组织并指畸形（STS），同时缺失Adamts5增加了STS的严重程度。因此，Adamts9在确保跨数字网络回归方面具有非冗余和合作的作用。这一新的等位基因将有助于研究ADAMTS9的其他生物学功能。
ADAMTS9 is the most conserved member of a large family of secreted metalloproteases having diverse functions. Adamts9 null mice die before gastrulation, precluding investigations of its roles later in embryogenesis, in adult mice or disease models. We therefore generated a floxed Adamts9 allele to bypass embryonic lethality. In this mutant, unidirectional loxP sites flank exons 5 through 8, which encode the catalytic domain, including the protease active site. Mice homozygous for the floxed allele were viable, lacked an overt phenotype, and were fertile. Conversely, mice homozygous for a germ-line deletion produced from the floxed allele by Cre-lox recombination did not survive past gastrulation. Hemizygosity of the deleted Adamts9 in combination with mutant Adamts20 led to cleft palate and severe white spotting as previously described. Previously, Adamts9 haploinsufficiency combined with either Adamts20 or Adamts5 nullizygosity suggested a cooperative role in interdigital web regression, but the outcome of deletion of Adamts9 alone remained unknown. Here, Adamts9 was conditionally deleted in limb mesoderm using Prx1-Cre mice. Unlike other ADAMTS single knockouts, limb-specific Adamts9 deletion resulted in soft-tissue syndactyly (STS) with 100% penetrance and concurrent deletion of Adamts5 increased the severity of STS. Thus, Adamts9 has both non-redundant and cooperative roles in ensuring interdigital web regression. This new allele will be useful for investigating other biological functions of ADAMTS9.
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影响因子：
30.8
作者：
Zeggini, Eleftheria;Scott, Laura J.;Saxena, Richa;Voight, Benjamin F.;Marchini, Jonathan L.;Hu, Tianle;de Bakker, Paul I. W.;Abecasis, Goncalo R.;Almgren, Peter;Andersen, Gitte;Ardlie, Kristin;Bostroem, Kristina Bengtsson;Bergman, Richard N.;Bonnycastle, Lori L.;Borch-Johnsen, Knut;Burtt, Noel P.;Chen, Hong;Chines, Peter S.;Daly, Mark J.;Deodhar, Parimal;Ding, Chia-Jen;Doney, Alex S. F.;Duren, William L.;Elliott, Katherine S.;Erdos, Michael R.;Frayling, Timothy M.;Freathy, Rachel M.;Gianniny, Lauren;Grallert, Harald;Grarup, Niels;Groves, Christopher J.;Guiducci, Candace;Hansen, Torben;Herder, Christian;Hitman, Graham A.;Hughes, Thomas E.;Isomaa, Bo;Jackson, Anne U.;Jorgensen, Torben;Kong, Augustine;Kubalanza, Kari;Kuruvilla, Finny G.;Kuusisto, Johanna;Langenberg, Claudia;Lango, Hana;Lauritzen, Torsten;Li, Yun;Lindgren, Cecilia M.;Lyssenko, Valeriya;Marvelle, Amanda F.;Meisinger, Christa;Midthjell, Kristian;Mohlke, Karen L.;Morken, Mario A.;Morris, Andrew D.;Narisu, Narisu;Nilsson, Peter;Owen, Katharine R.;Palmer, Colin N. A.;Payne, Felicity;Perry, John R. B.;Pettersen, Elin;Platou, Carl;Prokopenko, Inga;Qi, Lu;Qin, Li;Rayner, Nigel W.;Rees, Matthew;Roix, Jeffrey J.;Sandbaek, Anelli;Shields, Beverley;Sjogren, Marketa;Steinthorsdottir, Valgerdur;Stringham, Heather M.;Swift, Amy J.;Thorleifsson, Gudmar;Thorsteinsdottir, Unnur;Timpson, Nicholas J.;Tuomi, Tiinamaija;Tuomilehto, Jaakko;Walker, Mark;Watanabe, Richard M.;Weedon, Michael N.;Willer, Cristen J.;Illig, Thomas;Hveem, Kristian;Hu, Frank B.;Laakso, Markku;Stefansson, Kari;Pedersen, Oluf;Wareham, Nicholas J.;Barroso, Ines;Hattersley, Andrew T.;Collins, Francis S.;Groop, Leif;McCarthy, Mark I.;Boehnke, Michael;Altshuler, David
通讯作者：
Altshuler, David
影响因子：
4.5
作者：
Silver DL;Hou L;Somerville R;Young ME;Apte SS;Pavan WJ
通讯作者：
Pavan WJ
影响因子：
30.8
作者：
通讯作者：
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影响因子：
4.4
作者：
Clark, ME;Kelner, GS;Maki, RA
通讯作者：
Maki, RA
影响因子：
11.8
作者：
McCulloch, Daniel R.;Nelson, Courtney M.;Dixon, Laura J.;Silver, Debra L.;Wylie, James D.;Lindner, Volkhard;Sasaki, Takako;Cooley, Marion A.;Argraves, W. Scott;Apte, Suneel S.
通讯作者：
Apte, Suneel S.