TY - JOUR
T1 - A mutation in the viral sensor 2’-5’-oligoadenylate synthetase 2 causes failure of lactation
AU - Oakes, Samantha R.
AU - Gallego-Ortega, David
AU - Stanford, Prudence M.
AU - Junankar, Simon
AU - Au, Wendy Wing Yee
AU - Kikhtyak, Zoya
AU - von Korff, Anita
AU - Sergio, Claudio M.
AU - Law, Andrew M.K.
AU - Castillo, Lesley E.
AU - Allerdice, Stephanie L.
AU - Young, Adelaide I.J.
AU - Piggin, Catherine
AU - Whittle, Belinda
AU - Bertram, Edward
AU - Naylor, Matthew J.
AU - Roden, Daniel L.
AU - Donovan, Jesse
AU - Korennykh, Alexei
AU - Goodnow, Christopher C.
AU - O’Bryan, Moira K.
AU - Ormandy, Christopher J.
N1 - Funding Information:
This work was supported by grants from the Congress Directed Medical Research Program (BC995364 and DAMD17-01-1-0241), Cure Cancer Australia Foundation, NHMRC Australia (projects 1047149, Fellowships 1058356, 481310, 1043400), the Australian Research Council Discovery Project (DP110102288), Princeton University, NIH grant 1R01GM110161-01 (AK), Sidney Kimmel Foundation for Cancer Research (AK), Burroughs Wellcome Foundation (AK), Banque Nationale de Paris-Paribas Australia and New Zealand, Mostyn Family Foundation, Cue Clothing Co., Estee Lauder Australia, RT Hall Trust and Fellowships (ECF-13-08 and ECF-16-022) from the National Breast Cancer Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was made possible by extensive contributions of resources and expertise from the Australian Phenomics Network, including the Australian Phenomics Facility (and in particular Vicki Adams her role in screening), Australian National University Canberra, the Histopathology and Organ Pathology Service at University of Melbourne, the ES-Mouse Service at Monash University Melbourne and the Australian Genome Research Facility Brisbane, all funded in part by MNRF and NCRIS grants. We thank Yoichiro Iwakura from the Institute of Medical Science, University of Tokyo, for the Oas2 constructs, Ms. Gillian Lehrbach for assistance with tissue culture, Anaiis Zaratzian for assistance with histology and the staff of the Garvan Institute animal facilities in Moss Vale and Sydney.
Publisher Copyright:
© 2017 Oakes et al.
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85036607316&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85036607316&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1007072
DO - 10.1371/journal.pgen.1007072
M3 - Article
C2 - 29117179
AN - SCOPUS:85036607316
VL - 13
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 11
M1 - e1007072
ER -