A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.
A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.
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DOI：
10.1371/journal.pgen.1007072
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发表时间：
2017-11
期刊：
影响因子：
4.5
通讯作者：
Ormandy CJ
中科院分区：
文献类型：
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作者：
Oakes SR;Gallego-Ortega D;Stanford PM;Junankar S;Au WWY;Kikhtyak Z;von Korff A;Sergio CM;Law AMK;Castillo LE;Allerdice SL;Young AIJ;Piggin C;Whittle B;Bertram E;Naylor MJ;Roden DL;Donovan J;Korennykh A;Goodnow CC;O'Bryan MK;Ormandy CJ
我们确定了一个非同义突变Oas 2（I405 N），一个传感器的病毒双链RNA，从ENU诱变筛选，旨在发现新的基因参与乳腺发育。该突变导致健康小鼠产后泌乳失败，否则正常发育的乳腺，其特征是大大减少牛奶蛋白合成加上上皮细胞死亡，抑制增殖和强大的干扰素反应。在培养的HC-11或T47 D乳腺细胞中表达突变型而非野生型Oas 2，重现了在小鼠中观察到的表型和转录效应。该突变激活了OAS 2通路，表现为RNase L活性增加34倍，其作用依赖于RNase L和IRF 7、近端和远端通路成员的表达。这是第一次报告的病毒识别途径调节泌乳。使用ENU诱变小鼠，我们发现了一个家系与哺乳失败。在突变动物中，青春期和妊娠期的乳房发育似乎正常，但在产后立即激活泌乳失败，没有乳汁到达幼崽。泌乳失败伴随着乳蛋白合成大大减少，上皮细胞增殖减少，上皮细胞死亡增加和强有力的干扰素反应。发现病毒传感器Oas 2中的Oas 2（I405 N）中的非同义突变，并且突变Oas 2在乳腺细胞中的表达再现了这些表型。RNase L是OAS 2作用的最近端效应子，在突变小鼠的乳腺和表达突变OAS 2的乳腺细胞中被激活。RNA酶L或远端通路成员IRF 7的敲低阻止了这些作用，表明OAS 2中的突变引起了病毒信号通路的激活。这些结果表明，乳腺中的病毒检测可以防止泌乳。
We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation. Using ENU-mutagenesis in mice we discovered a pedigree with lactation failure. Mammary development through puberty and pregnancy appeared normal in mutant animals, but the activation of lactation failed in the immediate post partum period and no milk reached the pups. Failure of lactation was accompanied by greatly diminished milk protein synthesis, decreased epithelial cell proliferation, increased epithelial cell death and a robust interferon response. A non-synonymous mutation in Oas2 (I405N) in the viral sensor Oas2 was found and expression of mutant Oas2 in mammary cells recapitulated these phenotypes. RNase L, the most proximal effector of OAS2 action, was activated in the mammary glands of mutant mice and in mammary cells expressing mutant Oas2. Knockdown of RNase L, or the distal pathway member IRF7, prevented these effects, indicating that the mutation in OAS2 caused activation of the viral signaling pathway. These results show that viral detection in the mammary gland can prevent lactation.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
Biopython：用于计算分子生物学和生物信息学的免费 Python 工具。
DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Cock PJ;Antao T;Chang JT;Chapman BA;Cox CJ;Dalke A;Friedberg I;Hamelryck T;Kauff F;Wilczynski B;de Hoon MJ
通讯作者：
de Hoon MJ
影响因子：
16.8
作者：
Hoffmann HH;Schneider WM;Rice CM
通讯作者：
Rice CM
影响因子：
12.4
作者：
Castelli, JC;Hassel, BA;Youle, RJ
通讯作者：
Youle, RJ
影响因子：
--
作者：
Harris, J;Stanford, PM;Ormandy, CJ
通讯作者：
Ormandy, CJ