Megf10 regulates the progression of the satellite cell myogenic program

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada K1N 6N5.
The Journal of Cell Biology (Impact Factor: 9.83). 01/2008; 179(5):911-22. DOI: 10.1083/jcb.200709083
Source: PubMed


We identify here the multiple epidermal growth factor repeat transmembrane protein Megf10 as a quiescent satellite cell marker that is also expressed in skeletal myoblasts but not in differentiated myofibers. Retroviral expression of Megf10 in myoblasts results in enhanced proliferation and inhibited differentiation. Infected myoblasts that fail to differentiate undergo cell cycle arrest and can reenter the cell cycle upon serum restimulation. Moreover, experimental modulations of Megf10 alter the expression levels of Pax7 and the myogenic regulatory factors. In contrast, Megf10 silencing in activated satellite cells on individual fibers or in cultured myoblasts results in a dramatic reduction in the cell number, caused by myogenin activation and precocious differentiation as well as a depletion of the self-renewing Pax7+/MyoD- population. Additionally, Megf10 silencing in MyoD-/- myoblasts results in down-regulation of Notch signaling components. We conclude that Megf10 represents a novel transmembrane protein that impinges on Notch signaling to regulate the satellite cell population balance between proliferation and differentiation.

Download full-text


Available from: Chet E Holterman
  • Source
    • "Recessive mutations in MEGF10 (MIM 612453) were associated with early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD; MIM 614399) (Logan et al., 2011; Boyden et al., 2012). MEGF10 is expressed in quiescent and activated satellite cells and knock-down of Megf10 in mouse muscle resulted in satellite cell depletion (Holterman et al., 2007). EMARDD patient muscle showed reduced mean myofibre diameter and lacked PAX7 + nuclei (Logan et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The congenital myopathies are a diverse group of genetic skeletal muscle diseases, which typically present at birth or in early infancy. There are multiple modes of inheritance and degrees of severity (ranging from foetal akinesia, through lethality in the newborn period to milder early and later onset cases). Classically, the congenital myopathies are defined by skeletal muscle dysfunction and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. However, mutations in multiple different genes can cause the same pathology and mutations in the same gene can cause multiple different pathologies. This is becoming ever more apparent now that, with the increasing use of next generation sequencing, a genetic diagnosis is achieved for a greater number of patients. Thus, considerable genetic and pathological overlap is emerging, blurring the classically established boundaries. At the same time, some of the pathophysiological concepts underlying the congenital myopathies are moving into sharper focus. Here we explore whether our emerging understanding of disease pathogenesis and underlying pathophysiological mechanisms, rather than a strictly gene-centric approach, will provide grounds for a different and perhaps complementary grouping of the congenital myopathies, that at the same time could help instil the development of shared potential therapeutic approaches. Stemming from recent advances in the congenital myopathy field, five key pathophysiology themes have emerged: defects in (i) sarcolemmal and intracellular membrane remodelling and excitation-contraction coupling; (ii) mitochondrial distribution and function; (iii) myofibrillar force generation; (iv) atrophy; and (v) autophagy. Based on numerous emerging lines of evidence from recent studies in cell lines and patient tissues, mouse models and zebrafish highlighting these unifying pathophysiological themes, here we review the congenital myopathies in relation to these emerging pathophysiological concepts, highlighting both areas of overlap between established entities, as well as areas of distinction within single gene disorders. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.
    Full-text · Article · Dec 2014 · Brain
  • Source
    • "MEGF10 is required for mosaic spacing of retinal neurons via homotypic interaction with MEGF11 [9]. In skeletal muscle, high expression of MEGF10 in activated satellite cells as well as regulation of satellite cell functions by MEGF10 have been reported [10]. Recent studies have reported an association of MEGF10 with congenital myopathy in human. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MEGF10 is known to function as a myogenic regulator of satellite cells in skeletal muscle. Mutations in MEGF10 gene cause a congenital myopathy called early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Despite its biological importance in muscle physiology, transcriptional regulation of the MEGF10 gene is unknown. Here, we characterized the 5' flanking region of the human MEGF10 gene and showed that the role of myogenic basic helix-loop-helix factor (bHLH) myogenin in MEGF10 transcription in muscle cells. Myogenin was found to share a similar expression pattern with MEGF10 during muscle regeneration and to increase the promoter activity of the MEGF10 gene in C2C12 cells. Overexpression of myogenin led to upregulation of MEGF10 mRNA in C2C12 cells. Site-directed mutagenesis assays revealed that the conserved E-box element at the region -114/-108 serves as a myogenin-binding motif. Promoter enzyme immunoassays and chromatin immunoprecipitation analysis showed direct interaction between myogenin and the myogenin-binding motif in the MEGF10 promoter. Taken together, these results indicate that myogenin is a positive regulator in transcriptional regulation of MEGF10 in skeletal muscle.
    Preview · Article · Jul 2014 · Biochemical and Biophysical Research Communications
  • Source
    • "RBP-J QSC, ASC Co-activator of notch signaling Maintain satellite cell number Bjornson et al., 2012; Mourikis et al., 2012 MEGF10 QSC, ASC Activate Notch signaling Maintain satellite cell number Holterman et al., 2007 Collagen VI ECM for QSC Increased muscle stiffness Maintain satellite cell self- renewal Urciuolo et al., 2013 Hypoxia Outside of QSC Down-regulate miR-1/206 Surpresse MyoD expression Maintain satellite cell in quiescent state Liu et al., 2012 QSC, quiescent satellite cells; ASC, activated satellite cells; RC, reserve cells; ECM, extracelllular matrix. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult skeletal muscle possesses extraordinary regeneration capacities. After muscle injury or exercise, large numbers of newly formed muscle fibers are generated within a week as a result of expansion and differentiation of a self-renewing pool of muscle stem cells termed muscle satellite cells. Normally, satellite cells are mitotically quiescent and reside beneath the basal lamina of muscle fibers. Upon regeneration, satellite cells are activated, and give rise to daughter myogenic precursor cells. After several rounds of proliferation, these myogenic precursor cells contribute to the formation of new muscle fibers. During cell division, a minor population of myogenic precursor cells returns to quiescent satellite cells as a self-renewal process. Currently, accumulating evidence has revealed the essential roles of satellite cells in muscle regeneration and the regulatory mechanisms, while it still remains to be elucidated how satellite cell self-renewal is molecularly regulated and how satellite cells are important in aging and diseased muscle. The number of satellite cells is decreased due to the changing niche during ageing, resulting in attenuation of muscle regeneration capacity. Additionally, in Duchenne muscular dystrophy (DMD) patients, the loss of satellite cell regenerative capacity and decreased satellite cell number due to continuous needs for satellite cells lead to progressive muscle weakness with chronic degeneration. Thus, it is necessary to replenish muscle satellite cells continuously. This review outlines recent findings regarding satellite cell heterogeneity, asymmetric division and molecular mechanisms in satellite cell self-renewal which is crucial for maintenance of satellite cells as a muscle stem cell pool throughout life. In addition, we discuss roles in the stem cell niche for satellite cell maintenance, as well as related cell therapies for approaching treatment of DMD.
    Full-text · Article · Jan 2014 · Frontiers in Cell and Developmental Biology
Show more