QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 24 October 2007
doi: 10.1242/dev.008367

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Potthoff, M. J. Articles by Olson, E. N. Search for Related Content PubMed PubMed Citation Articles by Potthoff, M. J. Articles by Olson, E. N.

MEF2: a central regulator of diverse developmental programs

Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.

View larger version (18K): [in this window] [in a new window]   Fig. 1. Sequence conservation of MEF2. The percentage amino acid identity within the MADS, MEF2 and transcriptional activation domains of different MEF2 proteins from various organisms relative to human (h) MEF2A. N-termini are to the left.

View larger version (15K): [in this window] [in a new window]   Fig. 2. MEF2 as a central regulator of differentiation and signal responsiveness. MAP kinase signaling activates MEF2. Calcium-dependent signals also activate MEF2 by stimulating calcium-dependent kinases that phosphorylate class II HDACs, thereby promoting their dissociation from MEF2 and derepressing MEF2 target genes. MEF2 recruits numerous co-factors to drive the differentiation of the various cell types shown. Although MAPK and HDAC signaling pathways have been implicated in the modulation of numerous MEF2-dependent developmental programs, these signaling pathways have not yet been shown to operate in all the cell types under MEF2 control.

View larger version (21K): [in this window] [in a new window]   Fig. 3. Roles of MEF2 in Drosophila muscle development. (A) In the early mesoderm, MEF2 expression is activated by Twist, and MEF2 regulates downstream genes involved in cell migration, signaling and founder cell identity. (B) During differentiation of the somatic muscle lineage, Lame duck (LMD) activates MEF2 expression in a subset of muscle cells. DPP also regulates MEF2 expression via Twist and MAD/Medea. During late myogenesis, MEF2 autoactivates its own expression. MEF2 regulates hundreds of genes involved in contractility, neuromuscular junction formation, myoblast fusion, ion transport and metabolism. (C) In the developing dorsal vessel, MEF2 is regulated by GATA factors, Tinman, and by an as yet unidentified bHLH factor. MEF2 is essential for the expression of genes involved in cardiac contractility.

View larger version (10K): [in this window] [in a new window]   Fig. 4. MEF2 and mammalian skeletal myogenesis. Upstream inductive signals activate the expression of MYOD and MYF5, which activate the expression of myogenin in skeletal myocytes. Myogenin activates MEF2 expression, which feeds back on the myogenin promoter to amplify and maintain its expression. Myogenin and MEF2 also autoregulate their own promoters. MEF2, together with myogenic bHLH factors, activates genes involved in muscle differentiation. In addition, MEF2 activates HDAC9 expression, providing a negative-feedback loop that can be modulated by upstream signals that regulate HDAC9 phosphorylation. MEF2 also regulates the expression of the microRNA miR-1, which represses HDAC4 translation, thereby providing a positive-feedback loop for myogenesis.

View larger version (5K): [in this window] [in a new window]   Fig. 5. Control of anterior heart field development by MEF2C. MEF2C expression in the anterior heart field is controlled by GATA4, ISL1 and FOXH1, together with NKX2-5. MEF2C directly activates the expression of BOP, which is required for expression of HAND2, an essential regulator of anterior heart field development. Solid lines indicate direct regulatory interactions and dotted lines indicate regulatory interactions for which the underlying mechanism has not yet been defined.

View larger version (5K): [in this window] [in a new window]   Fig. 6. Control of neural crest development by MEF2C. Signaling by endothelin 1 (EDN1) through the ET-A receptor (EDNRA) activates MEF2C expression in the neural crest. MEF2C directly activates the expression of DLX5 and DLX6, which regulate the expression of HAND2. Together, these factors regulate the expression of genes required for craniofacial development.

View larger version (36K): [in this window] [in a new window]   Fig. 7. Regulation of bone development by MEF2. (A) High-magnification frontal view of Hematoxylin and Eosin-stained sections of mouse sternum. Left, wild-type trabeculated bone. MEF2C KO, chondrocyte-specific deletion of a conditional Mef2c allele, which results in a lack of bone owing to failure in chondrocyte hypertrophy. MEF2-engrailed super-repressor, when expressed in the cartilage of transgenic mice, also prevents ossification, whereas expression of a MEF2-VP16 super-activator results in the formation of excessive bone. (B) MEF2C and MEF2D promote chondrocyte hypertrophy and vascularization of developing bones by activating a network of transcription factors and signaling molecules involved in bone development. HDAC4 imposes negative control over the network by repressing the activity of MEF2 [adapted from Arnold et al. (Arnold et al., 2007)]. IHH, Indian hedgehog; PTHrP, parathyroid hormone-related peptide; RUNX2, runt related transcription factor 2.

View larger version (10K): [in this window] [in a new window]   Fig. 8. MEF2 functions in the endothelium. During embryogenesis, MEF2C expression in the endothelium is dependent on ETS factors, which bind an endothelial cell-specific enhancer. MEF2 activity is also modulated in the endothelium by survival factors, which act through the MAP kinase pathway [MEKK2/3 (also known as MAP3K2/3); MEK5 (also known as MAP2K5)], culminating on ERK5 (MAPK7), which associates with MEF2 directly to enhance transcriptional activity. MEF2 activates transcription of the Mmp10 gene, which encodes a matrix metalloproteinase that degrades endothelial cell junctions. HDAC7, which is expressed specifically in the developing endothelium, represses Mmp10 expression via MEF2. In the absence of HDAC7, MMP10 is upregulated and its inhibitor, TIMP1, is downregulated, leading to a loss in vascular integrity.