BBS Faculty Member - Sean Megason

Sean Megason

Department of Systems Biology

Harvard Medical School
200 Longwood Ave, WAB 536
Boston, MA 02115
Tel: 617-432-7441
Fax: 617-432-5012
Email: megason@hms.harvard.edu
Visit my lab page here.



The Megason Lab uses imaging-based systems biology to elucidate the systems level principles of animal development. We are particularly interested in long standing problems in embryology whose understanding has defied molecular reduction namely patterning, morphogenesis, and size control. We pursue these questions in the inner ear and spinal cord of zebrafish using a variety of techniques including genetics, microscopy, and modeling.

The Megason Lab has pioneered the use of in toto imaging for revealing the origin of biological form. With the completion of the genome projects, it is now clear that animals have very similar sets of genes. Yet, as is clear to any toddler at a zoo, the diversity of biological form, from the stripes of a zebra to the trunk of an elephant, that can be generated with this same toolbox is astounding. How can the linear sequence of information encoded by the A’s, G’s, C,’s and T’s in the genome be converted into elaborate tissues of the precise size, shape, and organization required for their function?

Biological form is generated during development as the seemingly simple egg elaborates into the morphologically complex embryo. I believe that the mechanistic principles that turn an egg into an embryo span many levels from molecules to cells to whole tissues. Developmental biologists have been quite successful in recent decades in determining molecular level mechanisms, such as the genes governing cell fate decisions, but have made comparatively little progress in other long standing questions in development such as patterning, morphogenesis, and size control. There are two reasons for this failure. One is that these questions cannot be answered using the reductionist logic of one gene, one function. Understanding these phenomena will require a more systems biological approach. The other reason progress has been slow is because the key mechanisms regulating these phenomena do not only occur at the molecular level but also occur at higher levels such as cell dynamics and tissue mechanics.

We have developed a technological approach called in toto imaging which is capable of capturing biological information across all these scales—molecular, cellular, tissue, and whole embryo—in a dynamic fashion. For in toto imaging, we use transgenic zebrafish embryos that are labeled with multiple colors of fluorescent proteins; high-resolution, timelapse confocal/2-photon microscopy is performed to generate image sets containing 100,000 images; and custom developed software called GoFigure is used to track all the cells and quantify molecular, cellular, and tissue level data. We are using in toto imaging in combination with mathematical and computational modeling to elucidate the multiscale principles controlling patterning, morphogenesis, and size control in the zebrafish inner ear and spinal cord.



Last Update: 6/2/2014



Publications

For a complete listing of publications click here.

 


 

Xiong F, Tentner AR, Huang P, Gelas A, Mosaliganti KR, Souhait L, Rannou R, Swinburne IA, Obholzer ND, Cowgill PD, Schier AF, Megason SG (2013). "Specified Neural Progenitors Sort to Form Sharp Domains after Noisy Shh Signaling", Cell, 153(3):550-561.

Mosaliganti KR, Noche RR, Xiong F, Swinburne IA, Megason SG. (2012). "ACME: Automated Cell Morphology Extractor for Comprehensive Reconstruction of Cell Membranes".
PLoS Comput Biol 8(12):e1002780

Obholzer N*, Swinburne IA*, Schwab E, Nechiporuk AV, Nicolson T, Megason SG (2012). "Rapid Positional Cloning of Zebrafish Mutations by Linkage and Homozygosity Mapping Using Whole Genome Sequencing."
Development 139, 4280-4290

Trinh LA, Hochgreb T, Graham M, Wu D, Ruf-Zamojski F, Jayasena CS, Saxena A, Hawk R, Gonzalez-Serricchio A, Dixson A, Chow E, Gonzales C, Leung HY, Solomon I, Bronner-Fraser M, Megason SG, and Fraser SE. (2011). "A versatile gene trap to visualize and interrogate the function of the vertebrate proteome",
Genes and Development 25:2306-2320, PMID 22056673

Megason SG, Srinivas S, Dickinson ME, Hadjantonakis AK. (2011). "Editorial Overview - Microscopy to mechanism across the scales of development",
Current Opinions in Genetics and Development 21:1-5 PMID 21996420

Megason SG. (2009). "In toto imaging of embryogenesis with confocal time-lapse microscopy".
Methods Mol Biol. 546:317-32.

Megason SG, Fraser SE. (2003) "Digitizing life at the level of the cell: high-performance laser-scanning microscopy and image analysis for in toto imaging of development."
Mech Dev. 2003 Nov;120(11):1407-20.



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