Brief Biography

It has been Dr. Ian Scott’s great pleasure to have the opportunity to return to Toronto to start his research group at The Hospital for Sick Children. Ian and his team focus on using the genetic and imaging tools available in the zebrafish embryo to study the earliest molecular and cellular events associated with heart development. As the genetic pathways that regulate heart formation are highly conserved across animal species, they are able to use the zebrafish embryo to model human congenital heart defects and heart failure. Ultimately, they hope to use these models to interrogate novel therapeutic approaches to these crippling diseases.

Outside the lab, Ian has enjoyed his time rediscovering snow after four years in Californiia. He enjoys sports (ice hockey and sailing as the seasons dictate), cooking and discovering Ontario wineries (a pleasant surprise after time spent in San Francisco).

Research Interests

• Pathways that specifiy heart progenitors
• Developmental regulation of heart morphogenesis and maturation
• Identification of novel genes that are required for heart development/heart disease
• Use of chemical genetic screens to find small molecules that can treat or improve zebrafish models of congenital heart disease

Research Activities

The Scott lab uses the zebrafish model organism to study vertebrate embryonic heart development. The zebrafish embryo is optically transparent, develops externally and rapidly (the heart starts beating at 24 hours after fertilization), and can be readily genetically and embryologically manipulated. His research team uses several approaches to examine how cardiac fate is first established, and how the heart later grows and develops. Perturbations of these events lead to congenital heart defects, which affect roughly one per cent of children born in Canada.

The lab is focused on on how cardiac fate is first established, and how the heart later grows and develops. Using the advantages of the zebrafish embryo, we employ genetic, embryological, live imaging and biochemical approaches to study in real time the earliest events of cardiovascular development. Current research topics include: 1) role of Aplnr signalling in migration of cardiac progenitors to the heart-forming region; 2) transcriptional control of early cardiac fate and migration; 3) regulation of second heart field (SHF) development; and 4) role of CCM3 signalling in cranial vasculature development.

Previous work on the zebrafish grinch mutant has highlighted the role of the Aplnr GPCR in early heart development. We have found that Aplnr signalling regulates migration of cardiac progenitors during gastrulation in a non cell-autonomous manner. Currently, we are examining how Aplnr signalling effectuates this key function. In a complementary set of approaches, we have found that a combination of the transcription factors Gata5 and Smarcd3/Baf60c is sufficient to direct cells placed in regions of the embryo normally fated to form non-cardiac structures to migrate to the heart-forming region and adopt a cardiovascular fate. Gata5/Smarcd3 therefore appear to have a remarkable remarkable "pro-cardiac progenitor" activity. We are currently evaluating the molecular pathways that act downstream of Gata5/Smarcd3.

Other research in the lab focuses on later aspects of cardiovascular development. We were among the grouped to show that development of the zebrafish heart is driven in part by addition of cells analogous to the mammalian second heart field (SHF). As defects in SHF development are causative of a large variety of congenital heart defects, we are using the zebrafish embryo to uncover novel regulators of SHF development. We have further uncovered a novel molecular pathway for pathogenesis of cranial cavernous malformations (CCMs), dilatations of the cranial vasculature that can lead to hemorrhages, seizures and death. We have found that CCM3 acts in an apparently CCM1/2 independent fashion in a zebrafish model of CCMs. Currently, we are examining the mechanism by which CCM3 regulates cranial vasculature development.

It is hoped that by combining genetic, embryological and imaging approaches we will gain a deeper understanding of the developmental processes that regulate heart development. In the future, we hope to apply this knowledge to therapeutic approaches for congenital and adult-onset cardiovascular disease.

Future Research Interests

• Application of cardiovascular progenitor cell pathways to vertebrate heart regeneration
• Use of chemical genetic approaches to both study heart development and explore using small molecules to alleviate zebrafish genetic models of congenital heart defects
• Use of gene trapping approaches to identify novel regulators of cardiovascular disease

External Funding

Canadian Institutes of Health Research (CIHR)
Natural Sciences and Engineering Research Council of Canada (NSERC)
Heart and Stroke Foundation of Canada (HSFC)
Canada Foundation for Innovation (CFI)

Achievements

2008
Maud Menten New Principal Investigator – Finalist. Canadian Institutes for Health Research

2005
New Opportunities Fund Award. Canadian Foundation for Innovation

Publications

Scott, I.C. (2012) Life Before Nkx2.5: Cardiovascular Progenitor Cells: Embryonic Origins and Development. Current Topics in Developmental Biology: Heart Development. 100, 1-33.

Paskaradevan, S. and Scott, I.C. (2012) The Aplnr GPCR signals independently of Gα¡/o proteins and cell-non-autonomously in the development of myocardial progenitor cells. Biology OPEN 1 (3), 275-85

Yoruk, B. and Scott, I.C. (2012) Ccm3 functions in a manner distinct from Ccm1 and Ccm2 in a zebrafish model of CCM vascular disease. Developmental Biology 362 (2), 121-131.

Lou, X., Deshwar, A.R., Crump, J.G. and Scott, I.C. (2011) Smarcd3b and Gata5 promote a cardiac progenitor fate in the zebrafish embryo. Development 138 (15), 3113-23.

Lazic, S. and Scott, I.C. (2011) Mef2cb regulates late myocardial cell addition from a second heart field-like population of progenitors in zebrafish. Developmental Biology 354 (1), 123-133.

Takeuchi, J.K.*, Lou, X.*, Alexander, J.M., Sugizaki, H., Delgado-Olguin, P., Holloway, A.K., Mori, A.D., Wylie, J.N., Munson, C., Zhu, Y., Zhou, Y.-Q., Yeh, R.-F., Henkelman, R.M., Harvey, R.P., Metzger, D., Chambon, P., Stainier, D.Y., Pollard, K.S., Scott, I.C. and Bruneau, B.G. (2011) Chromatin remodelling complex dosage modulates transcription factor function in heart development. Nature Communications 2, 187.

Yelon, D. And Scott, I.C. (2010) Cardiac development in the zebrafish. Heart Development and Regeneration, 2nd Edition. Editors: R. Harvey and N. Rosenthal (invited chapter).

Chi, N.C., Shaw, R.M., Jungblut, B., Huisken, J., Ferrer, T., Arnaout, R., Scott, I., Beis, D., Xiao, T., Baier, H., Jan, L.Y., Tristani-Firouzi, M. and Stainier, D.Y. (2008) Genetic and physiologic dissection of the vertebrate cardiac conduction system. PLoS Biol 6 (5), 1006-19.

Jin, S.-W., Herzog, W., Santoro, M.M., Mitchell, T.S., Frantsve, J., Jungblut, B., Beis, D., Scott, I.C., D’Amico, L.A., Ober, E.A., Verkade, H., Field, H.A., Chi, N.C., Wehman, A.M., Baier, H. and Stainier, D.Y. (2007) A transgene-assisted genetic screen identifies essential regulators of vascular development in vertebrate embryos. Developmental Biology 307 (1), 29-42.

Scott, I.C., Masri, B., D’Amico, L.A., Jin, S.-W., Jungblut, B., Wehman, A.M., Baier, H., Audigier, Y. and Stainier, D.Y.R. (2007) The G protein-coupled receptor Agtrl1b regulates early development of myocardial progenitors. Developmental Cell 12 (3), 403-413.

Beis, D., Bartman, T., Jin, S-W., Scott, I.C., D’Amico, L. A., Ober, E. A., Verkade, H., Frantsve, J., Field, H. A., Wehman, A., Baier, H., Tallafuss, A., Bally-Cuif, L.., Chen, J., Stainier, D. Y. R., and Jungblut, B. (2005) Genetic and cellular requirements for zebrafish atrio-ventricular cushion and valve development. Development 132(18), 4193-4204.

For a full list of Ian Scott's publications visit PubMed.