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Overlapping functions of the myogenic bHLH genes MRF4 and MyoD revealed in double mutant mice.
Development. 1998 Jul; 125(13):2349-58.D

Abstract

The myogenic basic helix-loop-helix (bHLH) genes - MyoD, Myf5, myogenin and MRF4 - exhibit distinct, but overlapping expression patterns during development of the skeletal muscle lineage and loss-of-function mutations in these genes result in different effects on muscle development. MyoD and Myf5 have been shown to act early in the myogenic lineage to establish myoblast identity, whereas myogenin acts later to control myoblast differentiation. In mice lacking myogenin, there is a severe deficiency of skeletal muscle, but some residual muscle fibers are present in mutant mice at birth. Mice lacking MRF4 are viable and have skeletal muscle, but they upregulate myogenin expression, which could potentially compensate for the absence of MRF4. Previous studies in which Myf5 and MRF4 null mutations were combined suggested that these genes do not share overlapping myogenic functions in vivo. To determine whether the functions of MRF4 might overlap with those of myogenin or MyoD, we generated double mutant mice lacking MRF4 and either myogenin or MyoD. MRF4/myogenin double mutant mice contained a comparable number of residual muscle fibers to mice lacking myogenin alone and myoblasts from those double mutant mice formed differentiated multinucleated myotubes in vitro as efficiently as wild-type myoblasts, indicating that neither myogenin nor MRF4 is absolutely essential for myoblast differentiation. Whereas mice lacking either MRF4 or MyoD were viable and did not show defects in muscle development, MRF4/MyoD double mutants displayed a severe muscle deficiency similar to that in myogenin mutants. Myogenin was expressed in MRF4/MyoD double mutants, indicating that myogenin is insufficient to support normal myogenesis in vivo. These results reveal unanticipated compensatory roles for MRF4 and MyoD in the muscle differentiation pathway and suggest that a threshold level of myogenic bHLH factors is required to activate muscle structural genes, with this level normally being achieved by combinations of multiple myogenic bHLH factors.

Authors+Show Affiliations

Department of Molecular Biology and Oncology, Department of Pathology, UT Southwestern Medical Center at Dallas, Dallas, Texas 75235, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9609818

Citation

Rawls, A, et al. "Overlapping Functions of the Myogenic bHLH Genes MRF4 and MyoD Revealed in Double Mutant Mice." Development (Cambridge, England), vol. 125, no. 13, 1998, pp. 2349-58.
Rawls A, Valdez MR, Zhang W, et al. Overlapping functions of the myogenic bHLH genes MRF4 and MyoD revealed in double mutant mice. Development. 1998;125(13):2349-58.
Rawls, A., Valdez, M. R., Zhang, W., Richardson, J., Klein, W. H., & Olson, E. N. (1998). Overlapping functions of the myogenic bHLH genes MRF4 and MyoD revealed in double mutant mice. Development (Cambridge, England), 125(13), 2349-58.
Rawls A, et al. Overlapping Functions of the Myogenic bHLH Genes MRF4 and MyoD Revealed in Double Mutant Mice. Development. 1998;125(13):2349-58. PubMed PMID: 9609818.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overlapping functions of the myogenic bHLH genes MRF4 and MyoD revealed in double mutant mice. AU - Rawls,A, AU - Valdez,M R, AU - Zhang,W, AU - Richardson,J, AU - Klein,W H, AU - Olson,E N, PY - 1998/6/4/pubmed PY - 1998/6/4/medline PY - 1998/6/4/entrez SP - 2349 EP - 58 JF - Development (Cambridge, England) JO - Development VL - 125 IS - 13 N2 - The myogenic basic helix-loop-helix (bHLH) genes - MyoD, Myf5, myogenin and MRF4 - exhibit distinct, but overlapping expression patterns during development of the skeletal muscle lineage and loss-of-function mutations in these genes result in different effects on muscle development. MyoD and Myf5 have been shown to act early in the myogenic lineage to establish myoblast identity, whereas myogenin acts later to control myoblast differentiation. In mice lacking myogenin, there is a severe deficiency of skeletal muscle, but some residual muscle fibers are present in mutant mice at birth. Mice lacking MRF4 are viable and have skeletal muscle, but they upregulate myogenin expression, which could potentially compensate for the absence of MRF4. Previous studies in which Myf5 and MRF4 null mutations were combined suggested that these genes do not share overlapping myogenic functions in vivo. To determine whether the functions of MRF4 might overlap with those of myogenin or MyoD, we generated double mutant mice lacking MRF4 and either myogenin or MyoD. MRF4/myogenin double mutant mice contained a comparable number of residual muscle fibers to mice lacking myogenin alone and myoblasts from those double mutant mice formed differentiated multinucleated myotubes in vitro as efficiently as wild-type myoblasts, indicating that neither myogenin nor MRF4 is absolutely essential for myoblast differentiation. Whereas mice lacking either MRF4 or MyoD were viable and did not show defects in muscle development, MRF4/MyoD double mutants displayed a severe muscle deficiency similar to that in myogenin mutants. Myogenin was expressed in MRF4/MyoD double mutants, indicating that myogenin is insufficient to support normal myogenesis in vivo. These results reveal unanticipated compensatory roles for MRF4 and MyoD in the muscle differentiation pathway and suggest that a threshold level of myogenic bHLH factors is required to activate muscle structural genes, with this level normally being achieved by combinations of multiple myogenic bHLH factors. SN - 0950-1991 UR - https://www.unboundmedicine.com/medline/citation/9609818/Overlapping_functions_of_the_myogenic_bHLH_genes_MRF4_and_MyoD_revealed_in_double_mutant_mice_ L2 - http://www.komp.org/ncbi.php?PMID=9609818 DB - PRIME DP - Unbound Medicine ER -