Part I: Vertebrate Organ Development: The Zebrafish Heart
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How does a fertilized egg develop into a complex multicellular organism such as a fly, mouse or human? During zebrafish heart development, for example, cells must proliferate, differentiate, move and come together to form a complex organ. Didier Stainier explains that zebrafish are an excellent model organism in which to address this question because their eggs are externally fertilized, they produce many offspring and the embryos and larvae are translucent. In addition, specific cells can be fluorescently labelled making it easier to image organ development in live fish. Taking advantage of these characteristics, Stainier and his colleagues performed large forward genetic screens to look for mutants in zebrafish heart development. Their findings provide insight into the evolution and development of the vertebrate heart.
In his second lecture, Stainier describes work from his lab investigating the formation of trabeculae in zebrafish hearts. Trabeculae are multicellular protrusions into the lumen of the ventricle that allow the heart to increase in muscle mass and thus pump more forcefully. Interestingly, trabeculae form only in the ventricle, not in the atrium, and only on the outer curvature of the ventricular lumen. For trabeculae to form, cardiomyocytes must delaminate from the outer layer of muscle cells and proliferate in the lumen. Stainier discusses how his lab identified factors regulating this process including the important roles of blood flow and contractility.
Gene function in zebrafish has been investigated by 1) randomly mutagenizing the genome, 2) knocking down genes with antisense oligos or 3) more recently, by specifically mutating a gene of interest with gene editing tools. Interestingly, phenotypes obtained by antisense knockdown are often more severe or different than those obtained by gene knockout. In his last lecture, Stainier presents work from his lab that compares knockdown vs knockout of the egfl7 gene in zebrafish (causing severe vs mild vascular defects) and asks why this difference in phenotypes occurs. He walks us through the experiments which show that in the case of egfl7, and numerous other genes, gene knockout effects are compensated by upregulated transcription of paralogous or related genes. This finding raises many questions about how this phenomenon occurs and Stainier’s group continues to investigate this and related questions.
Dr. Didier Stainier is a Director (Principal Investigator) in the Department of Developmental Genetics at the Max Planck Institute for Heart and Lung Research (MPI-HLR), in Bad Nauheim, Germany. His lab uses the zebrafish as a model to study development of the cardiovascular system and pancreas, and the mouse as a model for lung development. Prior to moving to the MPI-HLR, Stainier was Professor of Biochemistry and Biophysics at the University of California, San Francisco from 1995-2012.
Stainier received his PhD in Biochemistry and Molecular Biology from Harvard University where he worked in Wally Gilbert’s lab. As a post-doctoral fellow, Stainier moved to Mark Fishman’s lab at Massachusetts General Hospital where he initiated the studies on zebrafish cardiovascular development and function. Stainier was one of many scientists in Boston and Tübingen who carried out a huge screen for zebrafish mutants in early development and organogenesis. The screen was published in Development in 1996 and remains a useful resource to this day for labs studying fish. Stainier has since published over 200 papers on zebrafish development. Learn more about Stainier’s research.
- Deepak Srivastava Bench to Bedside: A Change of Heart: Embryo to Adult
- Jennifer Zallen iBioSeminar: Building Multicellular Structures during Development: New Roles for Toll Receptors
Stainier, D.Y.R. (2001). Zebrafish genetics and vertebrate heart formation. Nature Reviews Genetics. 2: 39-48.
Stainier, D.Y.R. (2002). A glimpse into the molecular entrails of endoderm formation. Genes & Development 16: 893-907.
Staudt, D. and Stainier D.Y.R. (2012). Uncovering the Molecular and Cellular Mechanisms of Heart Development with the Zebrafish. Annual Review of Genetics 46: 397-418.
Liu, J., Bressan, M., Hassel, D., Huisken, J., Staudt, D., Kikuchi, K., Poss, K.D., Mikawa, T., and Stainier, D.Y. (2010) A dual role for ErbB2 signaling in cardiac trabeculation. Development 137(22): 3867-3875.
Staudt, D.W., Liu, J., Thorn, K.S., Stuurman, N., Liebling, M., and Stainier, D.Y. (2014) High-resolution imaging of cardiomyocyte behavior reveals two distinct steps in ventricular trabeculation. Development 141(3): 585-593.
Jiménez-Amilburu, V., Rasouli, S.J., Staudt, D.W., Nakajima, H., Chiba, A., Mochizuki, N., Stainier, D.Y. (2016) In Vivo Visualization of Cardiomyocyte Apicobasal Polarity Reveals Epithelial to Mesenchymal-like Transition during Cardiac Trabeculation. Cell Rep. 17: 2687-2699.
Rasouli, S.J. and Stainier, D.Y.R. (2017). Regulation of cardiomyocyte behavior in zebrafish trabeculation by Neuregulin 2a signaling. Nat Commun. 8: 15281.
Rossi, A., Kontarakis, Z., Gerri, C., Nolte, H., Hölper, S., Krüger, M., Stainier, D.Y. (2015) Genetic compensation induced by deleterious mutations but not gene knockdowns. Nature 524(7564): 230-3.
El-Brolosy, M. and Stainier, D.Y. (2017) Genetic Compensation: A phenomenon in search of mechanisms. PLoS Genetics, in press.