Mef2 and the skeletal muscle differentiation program

Abstract

Mef2 is a conserved and significant transcription factor in the control of muscle gene expression. In cell culture Mef2 synergises with MyoD-family members in the activation of gene expression and in the conversion of fibroblasts into myoblasts. Amongst its in vivo roles, Mef2 is required for both Drosophila muscle development and mammalian muscle regeneration. Mef2 has functions in other cell-types too, but this review focuses on skeletal muscle and surveys key findings on Mef2 from its discovery, shortly after that of MyoD, up to the present day. In particular, in vivo functions, underpinning mechanisms and areas of uncertainty are highlighted. We describe how Mef2 sits at a nexus in the gene expression network that controls the muscle differentiation program, and how Mef2 activity must be regulated in time and space to orchestrate specific outputs within the different aspects of muscle development. A theme that emerges is that there is much to be learnt about the different Mef2 proteins (from different paralogous genes, spliced transcripts and species) and how the activity of these proteins is controlled.

Muscle A-kinase–anchoring protein-β–bound calcineurin toggles active and repressive transcriptional complexes of myocyte enhancer factor 2D

“…The MADS (minichromosome maintenance gene-1, agamous, deficiens, and serum response factor) box transcription factor MEF2 family is an important regulator of both tissue specification in development and the response to disease (1)(2)(3).…”

“…The activity of MEF2 transcription factors is extensively regulated by post-translational modifications, such that they serve as nodal integrators of intracellular signaling by Ca 2ϩ , mitogenactivated protein kinase, cyclic nucleotide, and phospholipiddependent pathways (1)(2)(3). One key regulator of MEF2 activity is the Ca 2ϩ /calmodulin-dependent protein phosphatase calcineurin (CaN), which can potentiate MEF2-dependent transcriptional activity through residue-specific dephosphorylation.…”

Roles of lncRNAs and circRNAs in regulating skeletal muscle development

“…Mice with a homozygous mutation in the MyoG gene survive foetal development but die immediately after birth, and have severely reduced skeletal muscle. 17,18 Myh is involved in the energy formation that pulls the actin filament across the myosin filament for muscular contraction. MEF2C mutant mice have an early embryonic lethal phenotype shortly after somite formation.…”

“…15,16 Skeletal muscle-specific deletion of MEF2C in mice results in disorganized myofibres and perinatal lethality. 17,18 Myh is involved in the energy formation that pulls the actin filament across the myosin filament for muscular contraction. 19,20 Pax3 and Pax7 can repress MyoD but do not impact the expression of Myf5, which together with Pax3/7, helps regulate myogenic differentiation of skeletal muscle.…”

MEF2C/miR‐133a‐3p.1 circuit‐stabilized AQP1 expression maintains endothelial water homeostasis

“…The myocyte enhancer factor 2 (MEF2) family transcription factors, consisting of MEF2A, ‐B, ‐C, and ‐D four members, play important roles in the differentiation, morphogenesis, and maintenance of muscle, cardiac, skeletal, vascular, neural, blood, and immune system through regulating cell differentiation, proliferation, apoptosis, migration, shape, and metabolism . MEF2C is required for neuronal differentiation and proper neuron distribution , craniofacial development , postnatal maturation of skeletal muscle and preservation of sarcomere integrity , and antigen receptor stimulated B‐cell proliferation and survival .…”