? ? Emery-Dreifuss muscular dystrophy (EDMD) results from mutations in two genes. Autosomal dominant EDMD, and infrequent autosomal recessive cases, result from mutations in LMNA. LMNA encodes A-type nuclear lamins, which are intermediate filament proteins associated with the inner nuclear membrane. Xlinked EDMD results from mutations in EMD, which encodes an integral protein of the nuclear envelope inner membrane called emerin. A commonly observed phenomenon in EDMD is defects in nuclear structure; however, little is known about how these structural defects relate to abnormal function. An emerging body of evidence demonstrates that the inside of the nucleus is connected to the cytoskeleton by a complex of interacting proteins termed the LING complex. These proteins include lamins, SUNs, which are transmembrane proteins of the inner nuclear membrane, and nesprins, some of which are transmembrane proteins localized to the outer nuclear membrane. Nesprins in turn can interact with cytoskeletal components such as actin. We hypothesize that mutations in the genes encoding A-type lamins and emerin cause a disruption of the LINC complex, which leads to abnormal nucleocytoskeletal connections and related defects in nuclear positioning and migration. Using a model system of fibroblasts undergoing polarization, we have obtained preliminary data showing that expression of lamin A mutants found in EDMD lead to nuclear movement defects.
In Aim 1 of this project, we will carefully examine nuclear migration and centrosome positioning in cells expressing A-type lamins with amino acid substitutions that cause EDMD and related muscle disorders, cells lacking A-type lamins and cells expressing A-type lamins with amino acid substitutions that cause different diseases.
In Aim 2, we will use fluorescence photobleaching techniques to determine the effects of mutations in A-type lamins on the dynamics of proteins of the LINC complex.
In Aim 3, to link the pathogenic processes in autosomal EDMD to X-linked EDMD, we will examine the effects of emerin on nuclear movement and LINC complex protein dynamics. As nuclear positioning and nuclear migration are of critical importance in muscle fiber organization and differentiation, these studies will establish if defects in nucleocytoplasmic interactions lead to functional anomalies that can underlie the pathogenesis of autosomal and X-linked EDMD. ? ? ?
| Chang, Wakam; Worman, Howard J; Gundersen, Gregg G (2015) Accessorizing and anchoring the LINC complex for multifunctionality. J Cell Biol 208:11-22 |
| Worman, Howard J; Dauer, William T (2014) The nuclear envelope: an intriguing focal point for neurogenetic disease. Neurotherapeutics 11:764-72 |
| Meinke, Peter; Mattioli, Elisabetta; Haque, Farhana et al. (2014) Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization. PLoS Genet 10:e1004605 |
| Chang, Wakam; Folker, Eric S; Worman, Howard J et al. (2013) Emerin organizes actin flow for nuclear movement and centrosome orientation in migrating fibroblasts. Mol Biol Cell 24:3869-80 |
| Worman, Howard J; Segil, Neil (2013) Nucleocytoplasmic connections and deafness. J Clin Invest 123:553-5 |
| Gundersen, Gregg G; Worman, Howard J (2013) Nuclear positioning. Cell 152:1376-89 |
| Worman, Howard J (2012) Nuclear lamins and laminopathies. J Pathol 226:316-25 |
| Lu, Jonathan T; Muchir, Antoine; Nagy, Peter L et al. (2011) LMNA cardiomyopathy: cell biology and genetics meet clinical medicine. Dis Model Mech 4:562-8 |
| Folker, Eric S; Ostlund, Cecilia; Luxton, G W Gant et al. (2011) Lamin A variants that cause striated muscle disease are defective in anchoring transmembrane actin-associated nuclear lines for nuclear movement. Proc Natl Acad Sci U S A 108:131-6 |
| Luxton, G W Gant; Gomes, Edgar R; Folker, Eric S et al. (2011) TAN lines: a novel nuclear envelope structure involved in nuclear positioning. Nucleus 2:173-81 |
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