Review
MEF2: a transcriptional target for signaling pathways controlling skeletal muscle growth and differentiation

https://doi.org/10.1016/S0955-0674(99)00036-8Get rights and content

Abstract

Skeletal muscle development involves a multistep pathway in which mesodermal precursor cells are selected, in response to inductive cues, to form myoblasts that later withdraw from the cell cycle and differentiate. The transcriptional circuitry controlling muscle differentiation is intimately linked to the cell cycle machinery, such that muscle differentiation genes do not become transcribed until myoblasts have exited the cell cycle. Members of the MyoD and MEF2 families of transcription factors associate combinatorially to control myoblast specification, differentiation and proliferation. Recent studies have revealed multiple signaling systems that stimulate and inhibit myogenesis by altering MEF2 phosphorylation and its association with other transcriptional cofactors.

Introduction

Skeletal muscle has become a model for understanding many fundamental principles of development, including mechanisms for cell fate specification, differentiation, morphogenesis and the antagonism between growth and differentiation. Many of the steps involved in the genesis of myoblasts from mesodermal precursors and their subsequent differentiation into multinucleate muscle fibers can now be viewed in molecular terms, with specific transcription factors and signaling systems controlling each developmental event (reviewed in 1, 2).

Members of two families of transcription factor play essential roles at virtually every step in the skeletal muscle development pathway. The MyoD family of basic helix-loop-helix (bHLH) proteins includes MyoD, myogenin, Myf5 and MRF4. The MEF2 family of MADS-box transcription factors includes MEF2A, -B, -C and –D. These two classes of transcription factor interact directly to establish a unique transcriptional code for skeletal muscle gene activation and also to regulate one anothers expression in mutually reinforcing regulatory circuits (reviewed in [3]).

In addition to their roles in the transcriptional activation of muscle-specific genes, the MyoD and MEF2 families serve as end points for the diverse intracellular signaling pathways that control myogenesis through modulation of the functions and the expression of these factors. These myogenic transcription factors also engage the cell cycle machinery to regulate the decision of myoblasts to divide or differentiate. Here, we review recent studies that further refine our understanding of the transcriptional circuits and signaling systems that control skeletal myogenesis and the central role of MEF2 factors in these developmental processes.

Section snippets

The partnership of MEF2 and MyoD

Previous studies have demonstrated that muscle-specific gene expression and myogenesis are regulated by combinatorial associations between myogenic bHLH proteins and MEF2 factors, and that the DNA-binding domains of these factors mediate their interactions [3]. MEF2 factors can only cooperate with heterodimers of myogenic bHLH proteins and E proteins, such as E12 and E47, not with E protein homodimers, which bind the same DNA sequence as MyoD–E12 heterodimers. An alanine and a threonine in the

Multiple partners for MEF2

Although MEF2 was initially identified as a muscle-restricted transcription factor that bound a conserved A/T-rich element in numerous muscle-specific genes, it is also expressed at high levels in neurons, as well as in T cells and fibroblasts. In each of these cell types, an important function of MEF2 is to transmit signals from the cell membrane to downstream immediate early genes and stress-response genes. The selection of genes regulated by MEF2 is determined by phosphorylation-dependent

Detection of MEF2 transcriptional activity in vivo using MEF2 sensor mice

In many cell types, there is a disparity between the expression of MEF2 mRNA, the level of MEF2 protein and MEF2 transcriptional activity. In an effort to identify cell types in vivo in which MEF2 protein was transcriptionally active, we created transgenic mice, referred to as MEF2 sensor mice, that harbor a lacZ transgene under the control of three tandem copies of the MEF2 consensus DNA binding site [12]. During early embryogenesis, these mice expressed lacZ in developing cardiac, skeletal

Control of MEF2 activity by transforming growth factor-β

Previous studies have shown that myogenic bHLH factors are inactive in cells exposed to transforming growth factor β (TGF-β), but they retain the ability to bind DNA under these conditions, suggesting that an essential myogenic cofactor might be the target of negative regulation by the TGF-β signaling pathway. De Angelis et al. [13] demonstrated that MEF2 undergoes translocation from the nucleus to the cytoplasm in myoblasts stimulated with TGF-β and this translocation can be overridden by a

Notch-dependent signaling to MEF2C

The transmembrane receptor Notch and its ligand Delta in Drosophila, and Jagged and serrate in vertebrates inhibit myogenesis. Previous studies have shown that Notch can block the ability of MyoD to activate myogenesis, suggesting that Notch activates a signaling system that targets MyoD directly or a cofactor for MyoD. The inhibitory activity of Notch appears to be directed at the MyoD basic region, but Notch does not alter MyoD DNA-binding activity. Given that MEF2 proteins interact with the

Regulation of MEF2 activity by MAP kinase signaling

Recent studies have demonstrated that MAP kinase signaling controls several steps in the myogenic pathway 15, 16 (Figure 2). Ectopic expression of the broad specificity MAP kinase phosphatase MKP-1 in C2C12 myoblasts is sufficient to interfere with the inhibitory influence of serum mitogens on myogenesis and allow precocious differentiation [15]. The target for MKP-1 action in proliferating myoblasts appears to be the MAP kinase p42Erk2, which is required for cyclin D1 expression. Upon

At the interface of muscle transcription and cell cycle control

In addition to their well-characterized roles in muscle cell specification and differentiation, members of the MyoD family of bHLH factors are intimately involved in controlling cell cycle progression and responsiveness of myoblasts to extracellular signals. Withdrawal from the cell cycle is a prerequisite for activation of the skeletal muscle differentiation program. The decision of a myoblast to divide or differentiate is controlled by the balance of positive and negative cell cycle

Regulation of muscle fiber type by MEF2

Adult skeletal muscle fibers can be generally classified into fast and slow twitch fiber types on the basis of contractile and metabolic properties, and gene expression patterns. The fiber-type characteristics of adult skeletal muscle are determined by the pattern of motor nerve innervation. Tonic motor nerve stimulation results in slow fiber gene expression, whereas lack of stimulation evokes a fast fiber gene expression program. It is thought that intracellular calcium levels are responsible

Conclusions

Our understanding of muscle development has reached a point at which many (or even most) of the components of the transcriptional circuitry and signaling pathways responsible for specification and differentiation of myoblasts have been identified. It is clear that the partnership of MEF2 and MyoD lies at the heart of many aspects of muscle development. Although we are beginning to understand how the expression and activity of these factors are regulated, many important questions remain. How, at

Acknowledgements

Work in the authors’ laboratory is supported by grants from the National Institutes of Health (NIH), the American Heart Association, the Robert A Welch Foundation and the Muscular Dystrophy Association. FJ Naya was supported by an NIH postdoctoral fellowship. We are grateful to J Page and A Tizenor for assistance with the manuscript.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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