Didier Stainier (MPI) 3: Genetic Compensation


Part 1: Vertebrate Organ Development: The Zebrafish Heart: Zebrafish heart development requires the orchestration of cell proliferation, differentiation, and movement. How is this complex process regulated? Part 2: Cardiac Trabeculation: Trabeculae are muscular ridges that form in the heart ventricle and allow it to pump more forcefully.  What controls the localization and development of these structures? Part 3: Genetic Compensation: Stainier explains why gene mutation via antisense oligos may result in a more severe phenotype than mutation via CRISPR-Cas9 or other gene editing tools. https://www.ibiology.org/ibioseminars/genetic-compensation.html Talk Overview: 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. Speaker Biography: 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 here: http://www.mpi-hlr.de/en/forschung/dept-iii.htmlFrom: iBiology

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