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Human Molecular Genetics Advance Access originally published online on January 10, 2006
Human Molecular Genetics 2006 15(4):637-651; doi:10.1093/hmg/ddi479
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Published by Oxford University Press 2006

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

Gisela Melcon1,{dagger}, Serguei Kozlov2,{dagger}, Dedra A. Cutler2,3,{dagger}, Terry Sullivan2, Lidia Hernandez2, Po Zhao1, Stephanie Mitchell1,3, Gustavo Nader1, Marina Bakay1, Jeff N. Rottman4, Eric P. Hoffman1,3 and Colin L. Stewart2,*

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

* To whom correspondence should be addressed at: Laboratory of Cancer and Developmental Biology, PO Box B, National Cancer Institute, Frederick, MD 21702, USA. Tel: +1 3018461755; Fax: +1 3018467117; Email: stewartc{at}ncifcrf.gov

Received October 6, 2005; Accepted January 5, 2006

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 was significantly delayed, whereas 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 hyper-phosphorylation 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, which 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, with regard to either the timing of exit from the cell cycle or terminal differentiation programs or both.

{dagger} The first three authors contributed equally to the work.


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