HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 1, 429-438, January 6, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/1/429    most recent M507440200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhao, P. Articles by Hoffman, E. P. Search for Related Content PubMed PubMed Citation Articles by Zhao, P. Articles by Hoffman, E. P. Social Bookmarking                      What's this?

Fgfr4 Is Required for Effective Muscle Regeneration in Vivo

DELINEATION OF A MyoD-Tead2-Fgfr4 TRANSCRIPTIONAL PATHWAY^*

Po Zhao, Giuseppina Caretti, Stephanie Mitchell, Wallace L. McKeehan¶, Adele L. Boskey||, Lauren M. Pachman**, Vittorio Sartorelli, and Eric P. Hoffman1

From the Research Center for Genetic Medicine, Children's National Medical Center, Washington, D. C. 20010, the Muscle Gene Expression Group, Laboratory of Muscle Biology, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, the ^¶Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030, the ^||Mineralized Tissues Laboratory, Hospital for Special Surgery, New York, New York 10021, and the ^**Molecular and Cellular Pathobiology Program, The Children's Memorial Research Center, Chicago, Illinois 60614

Fgfr4 has been shown to be important for appropriate muscle development in chick limb buds; however, Fgfr4 null mice show no phenotype. Here, we show that staged induction of muscle regeneration in Fgfr4 null mice becomes highly abnormal at the time point when Fgfr4 is normally expressed. By 7 days of regeneration, differentiation of myotubes became poorly coordinated and delayed by both histology and embryonic myosin heavy chain staining. By 14 days much of the muscle was replaced by fat and calcifications. To begin to dissect the molecular pathways involving Fgfr4, we queried the promoter sequences for transcriptional factor binding sites and tested candidate regulators in a 27-time point regeneration series. The Fgfr4 promoter region contained a Tead protein binding site (M-CAT 5'-CATTCCT-3'), and Tead2 showed induction during regeneration commensurate with Fgfr4 regulation. Co-transfection of Tead2 and Fgfr4 promoter reporter constructs into C2C12 myotubes showed Tead2 to activate Fgfr4, and mutation of the M-CAT motif in the Fgfr4 promoter abolished these effects. Immunostaining for Tead2 showed timed expression in myotube nuclei consistent with the mRNA data. Query of the expression timing and genomic sequences of Tead2 suggested direct regulation by MyoD, and consistent with this, MyoD directly bound to two strong E-boxes in the first intron of Tead2 by chromatin immunoprecipitation assay. Moreover, co-transfection of MyoD and Tead2 intron reporter constructs into 10T1/2 cells activated reporter activity in a dose-dependent manner. This activation was greatly reduced when the two E-boxes were mutated. Our data suggest a novel MyoD-Tead2-Fgfr4 pathway important for effective muscle regeneration.

Received for publication, July 8, 2005 , and in revised form, October 31, 2005.

^* This work was supported by grants from the Muscular Dystrophy Association U. S. A. (to E. P. H.), Department of Defense Grant W81XWH-04-01-0081 (to E. P. H.), and NIDDK, National Institutes of Health Grant DK35310 (to W. L. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Ave. NW, Washington, D. C. 20010. Tel.: 202-884-6011; Fax: 202-884-6014; E-mail: ehoffman{at}cnmcresearch.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Conte, N. Ainaoui, A. Delluc-Clavieres, M. P. Khoury, R. Azar, F. Pujol, Y. Martineau, S. Pyronnet, and A.-C. Prats Fibroblast growth factor 1 induced during myogenesis by a transcription-translation coupling mechanism Nucleic Acids Res., June 26, 2009; (2009) gkp550v1. [Abstract] [Full Text] [PDF]

				M. Lagha, T. Sato, L. Bajard, P. Daubas, M. Esner, D. Montarras, F. Relaix, and M. Buckingham Regulation of Skeletal Muscle Stem Cell Behavior by Pax3 and Pax7 Cold Spring Harb Symp Quant Biol, November 6, 2008; (2008) sqb.2008.73.006v1. [Abstract] [PDF]

				A. R. Grosso, A. Q. Gomes, N. L. Barbosa-Morais, S. Caldeira, N. P. Thorne, G. Grech, M. von Lindern, and M. Carmo-Fonseca Tissue-specific splicing factor gene expression signatures Nucleic Acids Res., September 1, 2008; 36(15): 4823 - 4832. [Abstract] [Full Text] [PDF]

				M. Lagha, J. D. Kormish, D. Rocancourt, M. Manceau, J. A. Epstein, K. S. Zaret, F. Relaix, and M. E. Buckingham Pax3 regulation of FGF signaling affects the progression of embryonic progenitor cells into the myogenic program Genes & Dev., July 1, 2008; 22(13): 1828 - 1837. [Abstract] [Full Text] [PDF]

				T. Yoshida MCAT Elements and the TEF-1 Family of Transcription Factors in Muscle Development and Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2008; 28(1): 8 - 17. [Abstract] [Full Text] [PDF]

				R. Yagi, M. J. Kohn, I. Karavanova, K. J. Kaneko, D. Vullhorst, M. L. DePamphilis, and A. Buonanno Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development Development, November 1, 2007; 134(21): 3827 - 3836. [Abstract] [Full Text] [PDF]

				X. Huang, C. Yang, Y. Luo, C. Jin, F. Wang, and W. L. McKeehan FGFR4 Prevents Hyperlipidemia and Insulin Resistance but Underlies High-Fat Diet Induced Fatty Liver Diabetes, October 1, 2007; 56(10): 2501 - 2510. [Abstract] [Full Text] [PDF]

				E. Greene, L. Mahishi, A. Entezam, D. Kumari, and K. Usdin Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia Nucleic Acids Res., May 11, 2007; 35(10): 3383 - 3390. [Abstract] [Full Text] [PDF]

				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]