Kollias HD, McDermott JC. Transforming growth factor-␤ and myostatin signaling in skeletal muscle.

We have cloned cDNA encoding a human transcription factor that belongs to the MEF2 (myocyte-specific enhancer-binding factor 2) subfamily of the MADS (MCM1-agamous-deficiens-serum response factor) gene family. This factor, which we have named MEF2C, binds specifically to the MEF2 element and activates transcription via this element.

The myocyte enhancer-binding factor 2 (MEF2) site is an essential element of many muscle-specific enhancers and promoters that binds nuclear proteins from muscle and brain. Recently, we have cloned a family of MEF2 transcription factors produced by two genes that, at the mRNA level, are broadly expressed and produce tissue-specific isoforms by posttranscriptional processes (Y.-T. Yu, R. E. Breitbart, L. B. Smoot, Y. Lee, V. Mahdavi, and B. Nadal-Ginard, Genes Dev. 6:1783Dev. 6: -1798Dev. 6: , 1992 Diverse cellular signals are involved in the induction of cell-type-specific genes that commit multipotent precursor cell lines to specific cell lineages. During the last decade, identification of factors responsible for the commitment of cells to a particular developmental fate has been one of the most productive aspects of developmental biology. The formation of skeletal muscle has proven to be a powerful model for the study of the mechanisms involved in both the production of cellular lineages as well as the establishment of the differentiated phenotype in vertebrates. Identification of the family of basic helix-loop-helix (bHLH) myogenic regulators (the MyoD family) as factors which can induce the myogenic program in a number of mesodermally derived cells has advanced our understanding of this process. The demonstration that they function as sequence-specific transcription factors, binding at the E-box present in many muscle enhancers and promoters, has become a paradigm for the analysis of cell determination and differentiation (16,38,50). However, despite the elegance and persuasiveness of the myogenesis model based on the MyoD family, it is clear that this family of regulators can neither be the exclusive myogenic determinants nor be wholly responsible for muscle-specific gene transcription. This is so because not all muscle-specific genes contain E-boxes, and even when they are present, they are not necessarily required for musclespecific gene regulation (4-7, 9, 18, 21, 25, 31, 36, 49, 53 Several families of transcription factors, in addition to the MyoD family of regulators, which mediate lineage determination and differentiation, such as the homeodomain (13) and MADS-box proteins (52), have been found to be expressed in muscle tissue. These factors have been proven to mediate lineage determination and differentiation in other systems and could provide new insights on the molecular mechanisms of myogenesis. In particular, the known homeotic function of MADS-box proteins in plants (11,26), together with their cooperative interaction with homeodomain proteins (23, 48), identifies them as candidates for evolutionarily conserved determinants of cell lineage. These interactions reveal a molecular strategy which through combinatorial mechanisms could generate a plethora of discrete signals necessary for the specification of a large number of different cell types by a limited number of factors.Recently, a new family of MADS-box transcription factors named the myocyte enhancer factor 2 (MEF2) genes have been identifi...

Myocyte enhancer factor 2 (MEF2) has been implicated in the complex hierarchical regulation of muscle-specific gene expression and differentiation. While the MyoD family members are able to initiate the skeletal muscle differentiation program, whether MEF2 is sufficient in directing skeletal muscle differentiation is still controversial. Furthermore, how MEF2 transactivates its target genes is not fully understood. It has been suggested that the interactions of MEF2 with other factors modify its transcriptional activity. Therefore, the identification of MEF2-interacting factors may be important in understanding the mechanism by which MEF2 activates its target genes. In this study, a mitogen-activated protein kinase (MAP kinase), ERK5/BMK1 was found to interact with MEF2 in a yeast two hybrid screen. The interaction was confirmed by a glutathione S -transferase-pull down assay and a co-immunoprecipitation study indicating that endogenous ERK5 and MEF2 interact with each other in vivo . The interacting domain of MEF2 was mapped to the N-terminus which contains the highly conserved MADS and MEF2 domains. Functionally, ERK5/BMK1 was able to phosphorylate MEF2 in vitro . Furthermore, when cotransfected with ERK5/BMK1, the transactivation capacity of MEF2 was enhanced. These results suggest that the functions of MEF2 could be regulated through ERK5/BMK1.

We have identified a mesoderm-specific Drosophila gene, desigatedD-mef2. The