Tube development and epithelial matrix biology in C. elegans
C. elegans, signaling, genetics, cell biology, epithelia, matrix.
Model organism research: why we love the worm!
The nematode Caenorhabditis elegans is a multicellular animal perfect for studying “single cell biology” because it has a very simple and well described anatomy that can be visualized by live imaging and that allows phenotypic analysis at single-cell resolution. C. elegans shares many genes and pathways with more complex organisms, and it is highly amenable to powerful forward and reverse genetic approaches to find genes involved in a process of interest. Many novel and conserved aspects of biology have been discovered in this system.
Description of Research
Organs are made up of tubes with different sizes and shapes that are specialized for their particular functions. The tiniest tubes, such as many mammalian capillaries, are unicellular, with the lumen actually inside the cell. More than half of all capillaries in the brain and in the renal glomeruli are unicellular tubes. Capillary defects are associated with cardiovascular diseases, stroke and age-associated dementia, and are a devastating side effect of diabetes, but little is known about how narrow capillaries are formed or protected.
My lab's research utilizes the “excretory” or renal-like system of C. elegans as a model system for studying the mechanisms that build, shape and stabilize narrow tubes. Using forward genetic screens, our lab has identified many genes that are important for building, shaping and stabilizing narrow tubes, and we are studying the pathways and mechanisms through which these act. Some of the questions we're addressing are:
How does auto-fusion promote seamless tube growth and shaping?
We showed that EGF-Ras-ERK signaling controls many aspects of unicellular tube morphology through a key target, the transmembrane fusogen AFF-1. AFF-1 fuses plasma membranes to convert an autocellular "seamed" tube into a "seamless" tube that lacks adherens junctions or tight junctions along its length. AFF-1 then mediates additional intracellular membrane-merging events that grow and shape the tube. We are studying the role of AFF-1 and other cytoskeletal changes and vesicle trafficking pathways that allow seamless tubes to adopt very complex, elongated shapes.
How does the luminal extracellular matrix shape and protect narrow tubes? What is the lipid connection?
Most tubes secrete various glycoproteins and lipoproteins into their developing lumens, and there is a growing appreciation of the importance of this luminal matrix in development and disease. We've identified several types of apically localized matrix proteins or lipophilic cargo binding proteins that are required to shape and protect the narrow duct and pore tubes, and to prevent them from bursting or leaking. We've also identified suppressor mutations that "fix" these tube problems. Current studies are examining links between lipid transporters and luminal matrix organization, and taking advantage of C. elegans' unique advantages to visualize the luminal matrix and understand its assembly and disassembly.
What controls tube delamination and trans-differentiation?
The excretory system is also an excellent model for studying junction remodeling and epithelial fate plasticity. At a specific stage of development, the excretory pore tube delaminates from the organ, loses epithelial identity, re-enters the cell-cycle and generates two neuronal daughters. The lab has identified mutants that perturb delamination, which should provide insight into mechanisms that trigger identity change and allow junction remodeling and delamination.
NOW RECRUITING STUDENTS! We have a variety of projects that could involve generating/analyzing whole genome sequence data, phenotyping/cloning new mutants, performing CRISPR-Cas9 genome editing, and/or conducting confocal, super-resolution or electron microscopy. See Meera if interested.
Jennifer Cohen (graduate student)
Michael Hart (Research Associate)
Alexandra Belfi (research specialist)
Susanna Birnbaum (research specialist)
Lily Zekavat (undergraduate student)
Robyn Howard-Barfield (1999-2004), now Group Leader at Catalent Pharma
Craig Stone (2003-2008), now Medical writer at EBSCO
Kelly Howell (2004-2010), now Scientist at SMA Foundation
Vincent Mancuso (2006-2011), now homemaker in NJ
Ishmail Abdus-Saboor (2007-2012), now faculty at UPenn Biology Dept.
Ranjana Kishore (1998-2002), now Staff Scientist at Caltech
Gautam Kao (1999-2003), now Researcher at Gothenburg U. (Sweden)
Kyunghee Koh (2001-2003), now faculty at Jefferson U.
Chris Rocheleau (2000-2005), now faculty at McGill U.
David Raizen (2001-2007), now faculty at UPenn
Olena Vatamaniuk (2004-2005), now faculty at Cornell U.
Jean Parry (2010-2014), now faculty at Georgian U.
Pu (Emily) Pu (2012-2017), now homemaker in China
Fabien Soulavie (2013-2018), now Researcher at IBDM, Marseille (France)
Nathaniel Dudley: PhD, UNC
David Garbe: PhD, UPenn
Laura Sherritt Girard: biotech industry
Jeff Doto: MCIT, UPenn
Yelena Bernstein: PharmD, Temple U.
Priti Batta: MD, Albert Einstein
Kelly Kraus: VMD, UPenn
Anne-Marie McKnight: MPH/PhD, Johns Hopkins
Kevin Cullison: MD, St Louis U.
Ariel Junio: biotech industry
Kate Palozola: PhD, UPenn
Brian Gantick: web design
Jennifer Cohen: in PhD program, UPenn
Hasreet Gill: in PhD program, Harvard
Rachel Forman-Rubinsky: in PhD program, U. Pittsburgh
Soulavie, F., Hall, D.H., Sundaram, M.V.: The AFF-1 exoplasmic fusogen is required for endocytic scission and seamless tube elongation. Nature Communications 9(1): 1741, May 2018.
Forman-Rubinsky, R., Cohen, J.D. and Sundaram, M.V. : Lipocalins are required for apical extracellular matrix organization and remodeling in Caenorhabditis elegans. Genetics 207: 625-642, October 2017.
Sundaram, M.V. and Cohen, J.D.: Time to make the doughnuts: Building and shaping seamless tubes. Seminars in Cell and Developmental Biology 67: 123-131, July 2017.
Soulavie, F. and Sundaram, M.V.: Auto-fusion and the shaping of neurons and tubes. Seminars in Cell and Developmental Biology 60: 136-145, December 2016.
Gill, H.K.*, Cohen, J.D.*, Ayala-Figueroa, J., Forman-Rubinsky, R., Poggioli, C., Bickard, K., Parry, J.M., Pu P., Hall, D.H. and Sundaram, M.V.: Integrity of narrow epithelial tubes in the C. elegans excretory system requires a transient luminal matrix PLoS Genetics 12(8): e1006205, August 2016.
Sundaram, M.V. and Buechner, M.: The Caenorhabditis elegans excretory system: a model for tubulogenesis, cell fate specification and plasticity. Genetics 203: 35-63, May 2016.
Mancuso, V.P., Parry, J. M., Storer, L., Poggioli, C., Nguyen, K. C. Q., Hall, D.H. and Sundaram, M.V: Extracellular leucine-rich repeat proteins are required to organize the apical extracellular matrix and maintain epithelial junction integrity in C. elegans. Development 139: 979-990, March 2012.
Abdus-Saboor, I., Mancuso, V.P., Murray, J.I., Palozola, K., Norris, C., Hall, D.H., Howell, K., Huang, K. and Sundaram, M.V: Notch and Ras promote sequential steps of excretory tube development in C. elegans. Development 138: 3545-3555, August 2011.
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Last updated: 10/18/2018
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