Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in genes encoding proteins of the nuclear envelope. Autosomal EDMD results from mutations in LMNA, which encodes A-type lamins, and X-linked EDMD from mutations in EMD, which encodes emerin. Mutations in genes encoding nesprins and SUNs are also associated with the EDMD phenotype. Nesprins and SUNs comprise the linker of the nucleoskeleton and cytoskeleton (LINC) complex that spans the nuclear membranes. The LINC complex connects the nuclear lamina, which binds to SUNs, to cytoskeletal components including actin, which bind to nesprins. Emerin also associates with lamins and nesprins and modifies LINC complex function. Alterations in expression or primary structure of the nuclear envelope proteins implicated in EDMD prevent the proper movement and positioning of nuclei in migrating cells. In parallel, there is an activation in signaling by the MAP kinase ERK1/2, which itself blocks nuclear movement. This has lead us to hypothesize that all of the nuclear envelope EDMD proteins contribute to a common cellular pathway that controls nuclear positioning, which is essential for proper skeletal muscle structure and directed migration of myogenic progenitors. We propose to test this hypothesis by examining links between nuclear movement, ERK1/2 activity, nuclear positioning in skeletal muscle, muscle progenitor cell migration and EDMD pathogenesis in three specific aims.
Aim 1 will involve a series of cell biological experiments designed to uncover how hyperactivated ERK1/2 prevents nuclear movement, including investigation of a previously uncharacterized hypothetical brake.
In Aim 2, we will determine how nuclear movement affects ERK1/2 activation by dissecting its relationship to ERK1/2 activity during physiological activation of the kinase and then testing if moving the nucleus is necessary and sufficient to regulate ERK1/2 signaling.
In Aim 3, we will first determine if EDMD-associated protein alterations that block nuclear movement interfere with myoblast fusion and differentiation in vitro. We will then use mouse models of EDMD to investigate the role A-type lamins and emerin on nuclear movement in regenerating skeletal muscle and to determine if alterations in these proteins block migration of myogenic progenitors into injured muscle. We will also determine if reducing ERK1/2 activity, which is elevated in skeletal muscle in EDMD, has effects on these processes. Overall, the proposed research will provide novel insights into the cellular pathology of EDMD, a poorly understood muscular dystrophy, and simultaneously uncover new information about nuclear movement, a process of broad significance to basic cell biology.

Public Health Relevance

Muscular dystrophies impact highly on public health, affecting tens of thousands of people in the United States. Emery-Dreifuss muscular is characterized by wasting of certain muscles and heart problems. This project is focused on defects in the fundamental cellular process of nuclear movement, which is essential for proper muscle development and function but abnormal in Emery-Dreifuss and related muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR068636-02
Application #
9134622
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Cheever, Thomas
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
$431,620
Indirect Cost
$148,264
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Zhu, Ruijun; Liu, Chenshu; Gundersen, Gregg G (2018) Nuclear positioning in migrating fibroblasts. Semin Cell Dev Biol 82:41-50
Saunders, Cosmo A; Harris, Nathan J; Willey, Patrick T et al. (2017) TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement. J Cell Biol 216:657-674
Belanto, Joseph J; Olthoff, John T; Mader, Tara L et al. (2016) Independent variability of microtubule perturbations associated with dystrophinopathy. Hum Mol Genet :
Chang, Wakam; Antoku, Susumu; Gundersen, Gregg G (2016) Wound-Healing Assays to Study Mechanisms of Nuclear Movement in Fibroblasts and Myoblasts. Methods Mol Biol 1411:255-67