Abstract
Establishment of skeletal muscle and neural cell types is controlled by families of myogenic and neurogenic basic helix-loop-helix (bHLH) proteins, respectively. Myogenic bHLH proteins have been shown to activate skeletal muscle transcription in collaboration with members of the myocyte enhancer factor-2 (MEF2) family of MCM1-agamous-deficiens-serum response factor (MADS)-box transcription factors, which are expressed in differentiated myocytes and neurons. Here, we show that the neurogenic bHLH protein MASH1 interacts with members of the MEF2 family and that this interaction, mediated by the DNA binding and dimerization domains of these factors, results in synergistic activation of transcription through either the MASH1 or the MEF2 DNA binding site. Consistent with their involvement in activation of neuronal gene expression, members of the MEF2 family are expressed in P19 embryonal carcinoma cells that have been induced to form neurons following treatment with retinoic acid. These results suggest that members of the MEF2 family perform similar roles in synergistic activation of transcription in myogenic and neurogenic lineages by serving as cofactors for cell type-specific bHLH proteins.
Highlights
Recent studies suggest that there are parallels between the mechanisms that regulate differentiation in the myogenic and neurogenic lineages [1]
Formation of skeletal muscle is controlled by a family of myogenic basic helix-loop-helix1 proteins, MyoD, myogenin, Myf5, and MRF4, which are expressed in skeletal muscle and can activate the complete program for skeletal muscle differentiation when expressed in several non-muscle cell types [2]
Given the high levels of myocyte-enhancer factor-2 (MEF2) expression in differentiated neurons and the similar roles of basic helix-loop-helix (bHLH) proteins in specifying myogenic and neurogenic cell fates, we examined whether MEF2 factors might act as cofactors for the neurogenic bHLH protein MASH1 in a manner analogous to their interaction with myogenic bHLH factors
Summary
Recent studies suggest that there are parallels between the mechanisms that regulate differentiation in the myogenic and neurogenic lineages [1]. Cell type-specific bHLH proteins like the myogenic and neurogenic factors form heterodimers with a family of ubiquitous bHLH factors known as E proteins, which includes the products of the E2A gene, E12 and E47, HEB, and the Drosophila daughterless gene product [7,8,9]. Recent studies have shown that members of the MEF2 family interact directly with heterodimers formed between myogenic bHLH proteins and E proteins and that the DNA binding and dimerization domains of these two different classes of transcription factors mediate this interaction [19, 20]. MASH1 and MEF2 Cooperativity that positively modulate the transcriptional activities of bHLH proteins in both myogenic and neurogenic lineages
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