Lmod2 piggyBac mutant mice exhibit dilated cardiomyopathy.
BACKGROUND
Leiomodin proteins, Lmod1, Lmod2 and Lmod3, are key regulators of the thin filament length in muscles. While Lmod1 is specifically expressed in smooth muscles, both Lmod2 and Lmod3 are expressed in striated muscles including both cardiac and skeletal muscles. We and others have previously shown that Lmod3 mainly function in skeletal muscles and the mutant mice display disorganized sarcomere. Lmod2 protein has been found to act as an actin filament nucleator in both cell-free assays and in cultured rat and chicken cardiomyocytes.


RESULTS
To better understand the function of Lmod2 in vivo, we have identified and characterized a piggyBac (PB) insertional mouse mutant. Our analysis revealed that the PB transposon inserts in the first exon of the Lmod2 gene and severely disrupts its expression. We found that Lmod2 (PB/PB) mice exhibit typical dilated cardiomyopathy (DCM) with ventricular arrhythmias and postnatal lethality. Electron microscope reveals that the Lmod2 (PB/PB) hearts carry disordered sarcomere, disarrayed thin filaments, and distorted intercalated discs (ICDs). Those ICDs display not only decreased convolutions, but also reduced electron-dense staining, indicating less ICDs component proteins in Lmod2 (PB/PB) hearts. Consistent with the phenotype, the expression of the ICD component genes, β-catenin and Connexin43, are down-regulated.


CONCLUSIONS
Taken together, our data reveal that Lmod2 is required in heart thin filaments for integrity of sarcomere and ICD and deficient mice exhibit DCM with ventricular arrhythmias and postnatal lethality. The Lmod2 (PB/PB) mutant offers a valuable resource for interrogation of pathogenesis and development of therapeutics for DCM.
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China.
Shuang
S
Li
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China.
Kaiqi
K
Mo
Cardiac Center, Children's Hospital of Fudan University, Shanghai, China.
Hong
H
Tian
Cardiac Center, Children's Hospital of Fudan University, Shanghai, China.
Chen
C
Chu
Cardiac Center, Children's Hospital of Fudan University, Shanghai, China.
Shuna
S
Sun
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China ; Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT USA.
Lei
L
Tian
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China ; Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT USA.
Sheng
S
Ding
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China.
Tong-Ruei
TR
Li
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China.
Xiaohui
X
Wu
Cardiac Center, Children's Hospital of Fudan University, Shanghai, China.
Fang
F
Liu
Shanghai Pediatric Congenital Heart Institute, Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
Zhen
Z
Zhang
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China ; Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT USA.
Tian
T
Xu
State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Fudan-Yale Center for Biomedical Research, Innovation Center for International Cooperation of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Children's Hospital of Fudan University, Fudan University, Shanghai, China.
Ling V
LV
Sun
Dilated cardiomyopathy; Intercalated discs; Leiomodin2 mutant; Sarcomere