Research in the Megeney lab is guided by the hypothesis that apoptotic proteins and pathways evolved core non-death cell function(s). Based on this guiding principle, we are investigating the mechanisms by which metacaspases/caspases direct cell fate/cell differentiation. In addition, we are exploring how these same proteins impact human disease, through an evolutionarily conserved targeting of protein aggregates.
In 2002, we published a paradigm setting study, whereby we demonstrated that the key cell death protein caspase 3 was required for skeletal muscle differentiation (Fernando et al. 2002 ProcNatlAcadSciUSA). Here we reported that loss of caspase 3 expression (via gene targeting) or caspase 3 activity (through the use of chemical inhibitors) led to a dramatic reduction in the formation of mature skeletal muscle myofibers. This paper provided the first evidence that a long lived cell type utilizes a pro-apoptotic protein to drive an adaptation or alteration that does not result in cell death or deconstruction of the cell. Although highly controversial at the time of publication, this paper is now widely recognized as one of the earliest documentations of a death centric protein engaging a non-death cell behavior.
Following the original work in skeletal muscle, we demonstrated that caspase 3 was instrumental in directing the differentiation program of committed cardiac progenitors and neural stem cell populations.â€¨ In 2010 we published two significant papers that address how metacaspase/caspase proteases manage cellular adaptation. In the first paper, we noted that differentiation of skeletal muscle progenitor cells was dependent on caspase mediated DNA strand breaks, an event that acts to reprogram gene expression in the differentiating cell. In the second paper, we reported that the single yeast caspase/metacaspase (yca1) is required for curtailing protein aggregation and thereby limiting insoluble protein deposition during times of stress. This latter study was a critical advance and suggests that perceived apoptotic or death centric proteins may have evolved from a core proteostasis function. Collectively, this work has overturned basic precepts in cell biology and given rise to an entirely new area of investigation explored by dozens of laboratories, i.e. the physiologic roles of apoptotic pathways/proteins.
Current research in the lab is focused on advancing both the basic biology of these discoveries as well as the impact on human disease. For example, we have noted that caspase activation is essential for the development of pathologic cardiac hypertrophy. As an approach to limit the development and progression of this common cardiac illness, we are continuing to investigate the molecular basis of caspase induced heart muscle cell growth. We are also actively investigating whether caspase enzymes retain the protein aggregate remodeling activity that we first noted in the metacaspase family. This avenue of research is addressing the supposition that caspases may target and dissolve protein aggregates that accumulate in various types of neurodegenerative disease, rather than contributing to disease progression.
Dr. Lynn Megeney is a Senior Scientist at the Ottawa Hospital Research Institute, where he also holds academic appointments in the Dept. of Medicine (Division of Cardiology) and the Dept. of Cellular and Molecular Medicine at the University of Ottawa. Dr. Megeney was the Holder of the Mach Gaennslen Chair in Cardiac Research from 2005 to 2011. Dr. Megeney has received numerous awards including an International Fellowship form the Chinese Academy of Sciences and the Queen Elizabeth II Diamond Jubilee Medal. Dr. Megeney's laboratory is supported by provincial, national and international funding agencies.
Dr. Megeney's research has had significant impact in an area of basic molecular biology with the discovery that cell death or cell suicide pathways play vital roles in normal biologic processes such as stem cell differentiation. Dr. Megeney has extended these early observations to demonstrate that cell death proteins evolved from non death roles in single cell organisms. Critically, the non-death roles for these signaling cascades are emerging as potent regulatory factors in human disease. In addition to the studies described above, Dr. Megeney's group was also the first to report evidence of a cardiac stem cell population in the post-natal heart. This basic science observation is now the focus of intense translational and commercial efforts in dozens of research groups around the world. In addition, these latter discoveries have formed the basis of a number of commercial ventures, whereby Dr. Megeney has been a scientific founder of three biotechnology companies.
Kolodziejczyk, S.M., Wang, L., Balaszi, K., DeRepentigny, Y., Kothary, R., and Megeney, L.A. (1999). MEF2 activity is upregulated during cardiac hypertrophy and is required for normal post natal growth of the myocardium. Curr. Biol. 9, 1203-1206.
Fernando, P.S., Kelly, J.F., Balazsi, K., Slack, R.S., and Megeney, L.A. (2002). Caspase 3 activity is required for skeletal muscle differentiation. Proc.Natl.Acad.Sci.USA. 99. 11025-11030.
Hierlihy, A, Seale, P.S, Lobe, C.G., Rudnicki, M.A., and Megeney, L.A. (2002). The post-natal heart contains a myocardial stem cell population. FEBS Letters. 530, 239-243.
Fernando, P.S., Brunette, S., and Megeney, L.A. (2005). Differentiation of neural stem cells depends on endogenous caspase 3 activity. FASEB J.,19, 1671-1673.
Abdul-Ghani, M., and Megeney, L.A. (2008). Rehabilitation of a contract killer: Caspase 3 directs stem cell differentiation. Cell Stem Cell, 2, 515-516.
Larsen, B.D., Rampalli, S., Burns, L., Dilworth, F.J. and Megeney, L.A. (2010). Caspase 3/Caspase activated DNase promote cell differentiation by inducing DNA strand breaks. Proc.Nat.Acad.Sci.USA. 107, 4230-4235.
Lee, R.E., Brunette ,S., Puente, L.G. and Megeney, L.A. (2010). Metacaspase Yca1 is required for clearance of insoluble protein aggregates. Proc.Natl.Acad.Sci.USA.107, 13348-13353.
Abdul-Ghani, M., Dufort, D., Stiles, R., De Repentigny, Y., Kothary, R. and Megeney, L.A. (2011). Wnt11 promotes cardiomyocyte development by caspase mediated suppression of canonical Wnt signals. Mol.Cell.Biol. 31, 163-178.
Shrestha, A., Puente, L., Brunette, S., and Megeney, L.A. (2013). The role of Yca1 in Proteostasis. Yca1 Regulates the Composition of the Insoluble Proteome. J. Proteomics, 81, 24-30.
Dick, S.A. and Megeney, L.A. (2013). Cell death proteins: An evolutionary role in cellular adaptation before the advent of apoptosis. Bioessays, 35, 974-983.
Putinski, C., Abdul-Ghani, M., Stiles, R., Brunette, S., Dick, S.A., Fernando, P.S., and Megeney, L.A. (2013). Intrinsic-mediated caspase activation is essential for cardiomyocyte hypertrophy. Proc.Natl.Acad.Sci.USA., 110, E4079-4087.