Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance.
Inheritance of the callipyge phenotype in sheep is an example of polar overdominance inheritance, an unusual mode of inheritance. To investigate the underlying molecular mechanism, we profiled the expression of the genes located in the Delta-like 1 homolog (Dlk1)-type III iodothyronine deiodinase (Dio3) imprinting region in mice. We found that the transcripts of the microRNA (miR) 379/miR-544 cluster were highly expressed in neonatal muscle and paralleled the expression of the Dlk1. We then determined the in vivo role of the miR-379/miR-544 cluster by establishing a mouse line in which the cluster was ablated. The maternal heterozygotes of young mutant mice displayed a hypertrophic tibialis anterior muscle, extensor digitorum longus muscle, gastrocnemius muscle, and gluteus maximus muscle and elevated expression of the DLK1 protein. Reduced expression of DLK1 was mediated by miR-329, a member of this cluster. Our results suggest that maternal expression of the imprinted miR-379/miR-544 cluster regulates paternal expression of the Dlk1 gene in mice. We therefore propose a miR-based molecular working model for polar overdominance inheritance.
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Yun-Qian
YQ
Gao
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Xin
X
Chen
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Pei
P
Wang
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Lei
L
Lu
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Wei
W
Zhao
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Chen
C
Chen
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Cai-Ping
CP
Chen
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Tao
T
Tao
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Jie
J
Sun
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Yan-Yan
YY
Zheng
Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Beijing 100029, China;
Jie
J
Du
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Chao-Jun
CJ
Li
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Zhen-Ji
ZJ
Gan
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China;
Xiang
X
Gao
School of Life Science, Nanjing Normal University, Nanjing 210009, China.
Hua-Qun
HQ
Chen
State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center and Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China; Innovation Center for Cardiovascular Disorders, Beijing Anzhen Hospital, Beijing 100029, China; zhums@nju.edu.cn.
Min-Sheng
MS
Zhu
D000818:Animals; D002135:Calcium-Binding Proteins; D005260:Female; D018392:Genomic Imprinting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C000605396:MIRN379 microRNA, mouse; C000605397:MIRN-544 microRNA, mouse; D035683:MicroRNAs
DLK1; callipyge; miR-379/miR-544 cluster; muscle hypertrophy