Role and Regulation of FRA-2 During Skeletal Muscle Development

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dc.contributor.advisorMcDermott, John Charles
dc.creatorAlli, Nezeka Sultana
dc.date.accessioned2015-01-26T14:35:55Z
dc.date.available2015-01-26T14:35:55Z
dc.date.copyright2014-06-09
dc.date.issued2015-01-26
dc.date.updated2015-01-26T14:35:55Z
dc.degree.disciplineBiology
dc.degree.levelDoctoral
dc.degree.namePhD - Doctor of Philosophy
dc.description.abstractRegulation of skeletal muscle development and regeneration is critical to all metazoans and also of clinical relevance as muscle wasting is manifested in a variety of disorders. The events contributing to development and regeneration of skeletal muscle are primarily controlled by members of the myogenic regulatory factors (MRF) and myocyte enhancer factor 2 (MEF2) transcription factor families. Secondary factors also exert effects on myogenesis such as the activator protein 1 (AP-1) transcription factor which has a complex role in the differentiation process. The AP-1 subunit Fra-2 has a role in skeletal muscle development and regeneration but it is less defined. Here, the role of Fra-2 in skeletal myogenesis was investigated thereby extending the study of AP-1 in muscle. It was determined that Fra-2 is regulated by the ERK 1/2 MAPK pathway via phosphorylation at S320 which is important for Fra-2 protein stability. Gain of function studies exploiting stability of Fra-2 achieved by phosphomimetic mutations impacted differentiation negatively. Conversely, loss of function using siRNAs resulted in precocious differentiation suggesting an overall inhibitory role for Fra-2 in myogenic cells. Intriguingly, it was observed that AP-1 is differentially expressed in a differentiated culture of C2C12 myogenic cells in that Fra-2 expression is restricted to monomucleated reserve cells and not in the differentiated myotubes. Furthermore, it was determined that Fra-2 is expressed in Pax7 positive satellite cells in a single muscle fibre culture model and that it binds to the promoter of the mustn1 gene which, in turn, is also a novel satellite cell marker. In conclusion, Fra-2 protein stability is regulated by phosphorylation of ERK 1/2 in myogenic cells and its expression in quiescent reserve cells and in satellite cells suggests a possible role for Fra-2 in maintaining the undifferentiated state in myogenic progenitor cells.
dc.identifier.urihttp://hdl.handle.net/10315/28212
dc.language.isoen
dc.rightsAuthor owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
dc.subjectMolecular biology
dc.subjectCellular biology
dc.subjectDevelopmental biology
dc.subject.keywordsSatellite cellsen_US
dc.subject.keywordsSkeletal muscleen_US
dc.subject.keywordsAP-1en_US
dc.subject.keywordsPhosphorylationen_US
dc.subject.keywordsERK 1/2 Signalingen_US
dc.titleRole and Regulation of FRA-2 During Skeletal Muscle Development
dc.typeElectronic Thesis or Dissertation

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