The focus of my research is the characterization of zebrafish mutations that affect cardiac development. This work currently centers on the study of three zebrafish mutants collectively referred to as the "big hearts" (valentine, heart of glass,santa). The hearts are huge, but thin-walled because the myocardium does not thicken as in the normal heart. The number of cells is not altered, implicating a defect in the concentric growth of the myocardium in these mutants. They have endocardium, but do not develop endocardial cushions, which give rise to valves.
The genes responsible for these mutations have been identified and we are currently looking at the relationship between these newly defined genes and the phenotype of the mutants. The similarity between the phenotypes of the three big hearts suggests the intriguing possibility of a common pathway. We can increase (by RNA injection) or decrease (by antisense morpholino oligomer injection) expression of these genes in the zebrafish, and together with biochemical approaches we hope to define the interactions between them.
Two of these three genes have never been described previously, and none of the three have been examined in the context of cardiac development. In addition, the development of the zebrafish heart is very similar to that of the early mammalian embryo so that any insights providedby this work will be extendable to human studies with relevance for human cardiac disease.
About John Mably
John Mably received his Ph.D. from the University of Toronto in 1994. He joined the laboratory of Mark Fishman at the Massachusetts General Hospital (CVRC) in 1996 where they used zebrafish as an animal model to study the genetics of cardiac development. John became a Principal Investigator in the CVRC in 2003 and joined the Cardiovascular Research department at Childrens Hospital in January 2007. Dr. Mably continues to employ zebrafish as an animal model to study cardiovascular development.
- Mwizerwa O, Das P, Nagy N, Akbareian SE, Mably JD, Goldstein AM. “Gdnf is mitogenic, neurotrophic, and chemoattractive to enteric neural crest cells in the embryonic colon.” Dev Dyn. 2011 Jun;240(6):1402-11. doi: 10.1002/dvdy.22630. Epub 2011 Apr 4. PMID:21465624
- Chan J, Mably JD. “Dissection of cardiovascular development and disease pathways in zebrafish.” Prog Mol Biol Transl Sci. 2011;100:111-53. Review. PMID:21377626
- Sogah VM, Serluca FC, Fishman MC, Yelon DL, Macrae CA, Mably JD. “Distinct troponin C isoform requirements in cardiac and skeletal muscle.” DevDyn. 2010 Nov;239(11):3115-23. PMID:20925115