Skip Navigation



Human Molecular Genetics Advance Access published online on January 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi479
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
15/4/637    most recent
ddi479v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Melcon, G.
Right arrow Articles by Stewart, C. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Melcon, G.
Right arrow Articles by Stewart, C. L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published by Oxford University Press 2006
Received October 6, 2005
Revised January 5, 2006
Accepted January 5, 2006

Article

Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration

Gisela Melcon 1, Serguei Kozlov 2, Dedra A. Cutler 3, Terry Sullivan 2, Lidia Hernandez 2, Po Zhao 1, Stephanie Mitchell 4, Gustavo Nader 1, Marina Bakay 1, Jeff N. Rottman 5, Eric P. Hoffman 4, and Colin L. Stewart 6 *

1 Research Center for Genetic Medicine, Children's National Medical Center, Washington DC
2 Laboratory of Cell and Developmental Biology, National Cancer Institute, Frederick, MD
3 Laboratory of Cell and Developmental Biology, National Cancer Institute, Frederick, MD; Department of Genetics, The George Washington University, Washington DC
4 Research Center for Genetic Medicine, Children's National Medical Center, Washington DC; Department of Genetics, The George Washington University, Washington DC
5 Department of Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave., Nashville, TN 37232-6300
6 Laboratory of Cancer and Developmental Biology, PO Box B, National Cancer Institute, Frederick, MD

* To whom correspondence should be addressed.
Colin L. Stewart, E-mail: stewartc{at}ncifcrf.gov


  Abstract

Emery Dreifuss Muscular Dystrophy (EDMD1) is caused by mutations in either the X-linked gene Emerin (EMD) or the autosomal Lamin A/C (LMNA) gene. Here we describe the derivation of mice lacking Emerin in an attempt to derive a mouse model for EDMD1. Although mice lacking Emerin show no overt pathology, muscle regeneration in these mice revealed defects. A bioinformatic array analysis of regenerating Emd null muscle revealed abnormalities in cell-cycle parameters and delayed myogenic differentiation, which were associated with perturbations to transcriptional pathways regulated by the Retinoblastoma (Rb1) and MyoD genes. Temporal activation of MyoD transcriptional targets were significantly delayed while targets of the Rb1/E2F transcriptional repressor complex remained inappropriately active. The inappropriate modulation of Rb1/MyoD transcriptional targets was associated with up-regulation of Rb1, MyoD and their co-activators/repressors transcripts, suggesting a compensatory effort to overcome a molecular block to differentiation at the myoblast/myotube transition during regeneration. This compensation appeared to be effective for MyoD-transcriptional targets, although was less effective for Rb1 targets. Analysis of Rb1 phosphorylation states showed prolonged hyperphosphorylation at key developmental stages in Emd null myogenic cells, both in vivo and in vitro. We also analyzed the same pathways in Lmna null muscle, which shows extensive dystrophy. Surprisingly Lmna null muscle did not show the same perturbations to Rb- and MyoD-dependent pathways. We did observe increased transcriptional expression of Lap2{alpha} and delayed expression of Rb1 that may regulate alternative transcriptional pathways in the Lmna null myoblasts. We suggest that the dominant LMNA mutations seen in many clinically disparate laminopathies may similarly alter Rb function, either with regards to the timing of exit from the cell cycle, or terminal differentiation programs, or both.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
J. Zhang, A. Felder, Y. Liu, L. T. Guo, S. Lange, N. D. Dalton, Y. Gu, K. L. Peterson, A. P. Mizisin, G. D. Shelton, et al.
Nesprin 1 is critical for nuclear positioning and anchorage
Hum. Mol. Genet., November 9, 2009; (2009) ddp499v2.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
G.-H. Liu, T. Guan, K. Datta, J. Coppinger, J. Yates III, and L. Gerace
Regulation of Myoblast Differentiation by the Nuclear Envelope Protein NET39
Mol. Cell. Biol., November 1, 2009; 29(21): 5800 - 5812.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
A. Mejat, V. Decostre, J. Li, L. Renou, A. Kesari, D. Hantai, C. L. Stewart, X. Xiao, E. Hoffman, G. Bonne, et al.
Lamin A/C-mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy
J. Cell Biol., May 4, 2009; 184(1): 31 - 44.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Muchir, J. Shan, G. Bonne, S. E. Lehnart, and H. J. Worman
Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins
Hum. Mol. Genet., January 15, 2009; 18(2): 241 - 247.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
J. M. Holaska
Emerin and the Nuclear Lamina in Muscle and Cardiac Disease
Circ. Res., July 3, 2008; 103(1): 16 - 23.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
A. Mulky, T. V. Cohen, S. V. Kozlov, B. Korbei, R. Foisner, C. L. Stewart, and V. N. KewalRamani
The LEM Domain Proteins Emerin and LAP2{alpha} Are Dispensable for Human Immunodeficiency Virus Type 1 and Murine Leukemia Virus Infections
J. Virol., June 15, 2008; 82(12): 5860 - 5868.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
T. Dechat, K. Pfleghaar, K. Sengupta, T. Shimi, D. K. Shumaker, L. Solimando, and R. D. Goldman
Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin
Genes & Dev., April 1, 2008; 22(7): 832 - 853.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. M. Ayala, T. Misteli, and F. E. Baralle
TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression
PNAS, March 11, 2008; 105(10): 3785 - 3789.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
L. Bengtsson and H. Otto
LUMA interacts with emerin and influences its distribution at the inner nuclear membrane
J. Cell Sci., February 15, 2008; 121(4): 536 - 548.
[Abstract] [Full Text] [PDF]

Home page
 J BiochemHome page
Y. Tsuchiya
Till Disassembly Do Us Part: A Happy Marriage of Nuclear Envelope and Chromatin
J. Biochem., February 1, 2008; 143(2): 155 - 161.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
C. L. Stewart, K. J. Roux, and B. Burke
Blurring the Boundary: The Nuclear Envelope Extends Its Reach
Science, November 30, 2007; 318(5855): 1408 - 1412.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
N. Leach, S. L. Bjerke, D. K. Christensen, J. M. Bouchard, F. Mou, R. Park, J. Baines, T. Haraguchi, and R. J. Roller
Emerin Is Hyperphosphorylated and Redistributed in Herpes Simplex Virus Type 1-Infected Cells in a Manner Dependent on both UL34 and US3
J. Virol., October 1, 2007; 81(19): 10792 - 10803.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
A. Muchir, P. Pavlidis, G. Bonne, Y. K. Hayashi, and H. J. Worman
Activation of MAPK in hearts of EMD null mice: similarities between mouse models of X-linked and autosomal dominant Emery Dreifuss muscular dystrophy
Hum. Mol. Genet., August 1, 2007; 16(15): 1884 - 1895.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
T. V. Cohen, O. Kosti, and C. L. Stewart
The nuclear envelope protein MAN1 regulates TGF{beta} signaling and vasculogenesis in the embryonic yolk sac
Development, April 1, 2007; 134(7): 1385 - 1395.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
J. M. Holaska, S. Rais-Bahrami, and K. L. Wilson
Lmo7 is an emerin-binding protein that regulates the transcription of emerin and many other muscle-relevant genes
Hum. Mol. Genet., December 1, 2006; 15(23): 3459 - 3472.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. Lammerding, L. G. Fong, J. Y. Ji, K. Reue, C. L. Stewart, S. G. Young, and R. T. Lee
Lamins A and C but Not Lamin B1 Regulate Nuclear Mechanics
J. Biol. Chem., September 1, 2006; 281(35): 25768 - 25780.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
X. Shi and D. J. Garry
Muscle stem cells in development, regeneration, and disease.
Genes & Dev., July 1, 2006; 20(13): 1692 - 1708.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
M. Bakay, Z. Wang, G. Melcon, L. Schiltz, J. Xuan, P. Zhao, V. Sartorelli, J. Seo, E. Pegoraro, C. Angelini, et al.
Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration
Brain, April 1, 2006; 129(4): 996 - 1013.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.