John C. McDermott

Research Focus

Our research interest concerns the basic regulatory mechanisms involved in cellular differentiation. This work is primarily undertaken using cardiac, skeletal and smooth muscle cells and neurons as model systems and is aimed at understanding the role of transcription factors in orchestrating tissue-specific gene expression and differentiation.

The genesis of this work was in identifying DNA binding proteins that are involved in transcriptional regulation during muscle development. Subsequent work explored the mechanisms by which these factors regulate cellular gene expression and differentiation. A main focus of our work has been the molecular cloning and characterization of a family of transcription factors (four genes, labelled MEF2A-D) that regulate the expression of many cardiac, smooth and skeletal muscle specific genes via the myocyte enhancer factor 2 (MEF2) cis- element. Based on their structural similarity, these genes belong to the MADS superfamily of DNA binding proteins that are involved in cell fate specification in many organisms ranging from yeasts to humans. Since the identification of the MEF2 gene family, further studies have been undertaken to assess the biological role of these genes during cardiac and skeletal muscle differentiation as well as in a variety of post-natal contexts such as cardiac disease (hypertrophy) and muscle regeneration.

It is well known that various intracellular signalling pathways potently regulate cell differentiation by targeting nuclear transcription factors. Moreover, muscle differentiation is extremely sensitive to the action of various growth factors. Therefore, our aim is to delineate the growth factor-activated signalling pathways that specifically converge on and modulate key transcriptional regulators such as MEF2 proteins during myogenesis. We are currently dissecting the effects of kinase mediated phosphorylation of MEF2 protein in order to fully understand how it serves as a nuclear sensor of growth factor -activated signalling pathways. In this regard we have reported a key role of the p38 MAP kinase pathway in targeting MEF2 in the somites during embryogenesis.  Included in this post translational analysis of MEF2 function is the identification of MEF2 interacting proteins using state of the art tools in Mass Spectrometry. Studies are also ongoing to determine the contribution of other transcriptional regulators such as the Fra2 subunit of the AP-1 complex and the Smad7 protein to the myogenic program in cardiac and skeletal muscle cells. This work is supported by the Canadian Institutes for Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC) of Canada and the Heart and Stroke Foundation of Canada (HSF).

Sub-Disciplines

Animal Biology/Physiology, Cell-Signaling, Molecular Biology

Research Areas