Mutations in the outer nuclear membrane proteins Nesprin 1 and 2 may be involved in the pathogenesis of Emery-Dreifuss muscular dystrophy (EDMD)-like phenotypes, including cardiomyopathy and dilated cardiomyopathy (DCM). Nesprins belong to a newly discovered family of spectrin-repeat proteins, composed of four members. Nesprin 1 and 2 are believed to anchor nuclei to actin filaments, and are ubiquitously expressed. To investigate functions of Nesprin 1 and 2, we have generated floxed and global knockout mice of both Nesprin 1 and 2. Our studies reveal that Nesprin 2 global knockout mice are viable and have no obvious basal phenotype, whereas over half of Nesprin 1 global knockout (Nesprin 1-/-) mice die perinatally. Remaining Nesprin 1-/- survivors have reduced body weight before three months of age and compromised exercise capacity. Consistent with data from others, we have found 100% perinatal lethality in double knockout mice for Nesprin 1 and 2. Histological analyses of skeletal muscle in Nesprin 1-/- mice and Nesprin 1 and 2 double knockout mice revealed abnormal positioning of non-synaptic nuclei and the disappearance of clusters of synaptic nuclei. We also observed that Nesprin 1-/- mice display abnormal shape and positioning of cardiomyocyte nuclei. In addition, we observed upregulation of protein levels of SUN1, a Nesprin 1 binding partner and an inner nuclear membrane protein, in Nesprin 1-/- heart samples. This 5 year proposal is to investigate the role of Nesprin 1 and 2 in cardiac nuclear position, nuclear membrane structure, and cardiac function by analysis of mutant mice and cells derived from them. Our unique ability to genetically ablate Nesprins in mouse cardiomyocytes, combined with the ability to test molecular and physiological functions in the whole animal, isolated papillary muscles, and cultured cardiomyocytes, will provide novel information as to the function of Nesprins in cardiac structure, function and disease.
Recent data suggest that mutations in Nesprin 1 and 2 may be involved in the pathogenesis of Emery-Dreifuss muscular dystrophy (EDMD)-like phenotypes including cardiomyopathy and dilated cardiomyopathy (DCM). Our proposed studies will help us to understand biological functions of Nesprin 1 and 2 in cardiac structure and function. The proposed studies will also help us gain insight into mechanisms by which mutations in Nesprin 1 are involved in the pathogenesis of DCM, thereby improving our general understanding of DCM.
|Stroud, Matthew J; Fang, Xi; Zhang, Jianlin et al. (2018) Luma is not essential for murine cardiac development and function. Cardiovasc Res 114:378-388|
|Hirai, Maretoshi; Arita, Yoh; McGlade, C Jane et al. (2017) Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation. J Clin Invest 127:569-582|
|Hirai, Maretoshi; Chen, Ju; Evans, Sylvia M (2016) Generation and Characterization of a Tissue-Specific Centrosome Indicator Mouse Line. Genesis 54:286-96|
|Lange, Stephan; Gehmlich, Katja; Lun, Alexander S et al. (2016) MLP and CARP are linked to chronic PKC? signalling in dilated cardiomyopathy. Nat Commun 7:12120|
|Mu, Yongxin; Jing, Ran; Peter, Angela K et al. (2015) Cypher and Enigma homolog protein are essential for cardiac development and embryonic survival. J Am Heart Assoc 4:|
|Guimarães-Camboa, Nuno; Stowe, Jennifer; Aneas, Ivy et al. (2015) HIF1? Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes. Dev Cell 33:507-21|
|Sheikh, Farah; Lyon, Robert C; Chen, Ju (2015) Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease. Gene 569:14-20|
|Mastrototaro, Giuseppina; Liang, Xingqun; Li, Xiaodong et al. (2015) Nebulette knockout mice have normal cardiac function, but show Z-line widening and up-regulation of cardiac stress markers. Cardiovasc Res 107:216-25|
|Banerjee, Indroneal; Zhang, Jianlin; Moore-Morris, Thomas et al. (2014) Targeted ablation of nesprin 1 and nesprin 2 from murine myocardium results in cardiomyopathy, altered nuclear morphology and inhibition of the biomechanical gene response. PLoS Genet 10:e1004114|
|Chapman, Mark A; Zhang, Jianlin; Banerjee, Indroneal et al. (2014) Disruption of both nesprin 1 and desmin results in nuclear anchorage defects and fibrosis in skeletal muscle. Hum Mol Genet 23:5879-92|
Showing the most recent 10 out of 22 publications