The nuclear envelope (NE) in eukaryotic cells separates nuclear and cytoplasmic compartments. The NE is comprised of an inner nuclear membrane (INM) and an outer nuclear membrane (ONM), which are lined with numerous proteins including those of the LInker-complex between the Nucleoskeleton and the Cytoskeleton (LINC). Mutations in several LINC members cause cardiomyopathies. Luma is a newly discovered member of the LINC complex in the INM. A single amino acid substitution of serine 358 to leucine (S358L) in Luma causes an autosomal-dominant, fully penetrant, cardiomyopathy. Luma interacts with other members of the LINC complex that reside in the INM, including Emerin, Lamins, and SUN2. Luma may play a role in Emerin localization, as HeLa cells depleted of Luma by RNA interference exhibit altered localization of Emerin and a reduction in Emerin levels. Another partner of Lama, LaminA/C directly interacts with chromosomes, and mutations in Lamin result in aberrant chromosome positioning and correlated changes in gene expression. The foregoing results have led us to the hypothesis that Luma plays a key role in cardiomyocyte nucleoskeletal and cytoskeletal integrity, chromosome positioning, and gene expression, and that the S358L mutation in Luma impairs specific aspects of Luma function to lead to cardiomyopathy. Accordingly, our Specific Aims are: 1) To characterize roles of Luma in developing and adult cardiomyocytes by elucidating Luma's subcellular localization and interaction partners, and by performing detailed histological and physiological analyses of cardiac specific Luma knockout mouse models utilizing a floxed allele of Luma. 2) To elucidate molecular mechanisms underlying cardiomyopathy consequent to the S358L mutation in Luma by detailed histological and physiological analyses of a Luma S358L knock-in mouse model. 3) To investigate mechanisms by which the Luma S358L mutation impacts human cardiomyocyte function, utilizing human induced pluripotent stem cell (iPSC) and human embryonic stem cell (hESC)-derived Luma- mutant cardiomyocytes.
While it is clear that mutations in Luma result in fully penetrant cardiomyopathy, little is known as to the role of Luma in cardiomyocytes or cardiac tissue, or how the Luma mutation leads to cardiomyopathy. Our proposed studies are aimed at understanding the role of Luma in cardiac muscle structure and function and to gain insights into mechanisms by which mutations in Luma cause cardiomyopathy.
| Veevers, Jennifer; Farah, Elie N; Corselli, Mirko et al. (2018) Cell-Surface Marker Signature for Enrichment of Ventricular Cardiomyocytes Derived from Human Embryonic Stem Cells. Stem Cell Reports 11:828-841 |
| 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 |
| Boogerd, Cornelis J; Zhu, Xiaoming; Aneas, Ivy et al. (2018) Tbx20 Is Required in Mid-Gestation Cardiomyocytes and Plays a Central Role in Atrial Development. Circ Res 123:428-442 |
| Moore-Morris, Thomas; Cattaneo, Paola; Guimarães-Camboa, Nuno et al. (2018) Infarct Fibroblasts Do Not Derive From Bone Marrow Lineages. Circ Res 122:583-590 |
| Fang, Xi; Bogomolovas, Julius; Wu, Tongbin et al. (2017) Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy. J Clin Invest 127:3189-3200 |
| Ma, Xiaolong; Chen, Chao; Veevers, Jennifer et al. (2017) CRISPR/Cas9-mediated gene manipulation to create single-amino-acid-substituted and floxed mice with a cloning-free method. Sci Rep 7:42244 |
| Guimarães-Camboa, Nuno; Cattaneo, Paola; Sun, Yunfu et al. (2017) Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo. Cell Stem Cell 20:345-359.e5 |
| 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 |
| Wu, Tongbin; Mu, Yongxin; Bogomolovas, Julius et al. (2017) HSPB7 is indispensable for heart development by modulating actin filament assembly. Proc Natl Acad Sci U S A 114:11956-11961 |
| Fang, Xi; Stroud, Matthew J; Ouyang, Kunfu et al. (2016) Adipocyte-specific loss of PPAR? attenuates cardiac hypertrophy. JCI Insight 1:e89908 |
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