Tubular organ development in C. elegans
C. elegans, signal transduction, Ras, genetics, tube development.
Description of Research
During embryonic development, multipotent cells must choose among various possible fates, and then differentiate and join together with appropriate neighbors to form functional organ systems. My research utilizes the “excretory” or renal system of the nematode worm Caenorhabditis elegans as a model system for studying the formation of tubular organs. C. elegans has many advantages for such studies, including a very simple and well described anatomy that allows phenotypic analysis at a single-celled resolution – for example, the worm’s renal system consists of only three connected single-celled tubes! C. elegans also has a sequenced genome containing many of the same genes found in more complex organisms, and it is highly amenable to powerful forward and reverse genetic approaches to find genes involved in a process of interest. We are identifying genes important for cells to adopt renal fates, form unicellular tubes and connect with one another to form a functional renal conduit, as well as genes that modulate the signal transduction pathways that control these processes.
EGF-Ras signaling and cell fate specification
The EGFR-Ras-ERK signaling pathway controls tube cell fate and morphology within the excretory organ. This pathway is also used to control many other developmental events, and a major question concerns the downstream targets of this pathway, how cell-type appropriate targets are chosen, and how these targets elicit specific responses. The lab has identified and is characterizing a number of potential ERK targets important for morphogenesis of the duct into an elongated, seamless tube. We've also identified proteins that modulate EGF signaling and are seeking to understand how they work.
EGF-Ras signaling and junction remodeling
The tubular cells of the excretory system are 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. We found that EGF-Ras signaling in the duct cell is required for successful delamination of the pore cell; thus, Ras acts cell non-autonomously to permit delamination. The lab has identified other mutants that perturb delamination and is trying to identify the mechanisms by which Ras signaling in an epithelial cell can facilitate delamination of a neighbor.
Critical roles for the apical extracellular matrix
Through genetic screening for mutants that disrupt tube integrity, we identified several types of apically localized transmembrane or secreted proteins that are required to organize the apical extracellular matrix and maintain junction connectivity. Current studies are examining the links between apical matrix and junctions, and between apical matrix and EGF signaling, and testing whether modulation of apical matrix contributes to programmed junction remodeling and delamination.
Please see Meera about possible projects
Hasreet Gill (undergraduate assistant, 2012-present)
Emily Pu (postdoctoral fellow, 2012-present)
Fabien Soulavie (postdoctoral fellow, 2013-present)
Rachel Forman-Rubinsky (research specialist, 2014-present)
Senait Bekele (undergraduate assistant, 2014-present)
Ranjana Kishore (postdoc, 1998-2002), Staff scientist, Wormbase, Caltech
Nate Dudley (research specialist, 1998-2000), went on to PhD
David Garbe (research specialist, 1998-2001), went on to PhD
Robyn Howard Barfield (grad student, 1999-2004), Staff scientist, Redwood Biosciences
Gautam Kao, (postdoc, 1999-2004), Research Associate, Gothenburg U. Sweden
Laura Sherritt (research specialist, 2000-2001), went on to industry
Christian Rocheleau (postdoc 2000-2005), Assoc Professor, McGill U.
Kyunghee Koh (postdoc, 2001-2003), Asst Professor, Jefferson U.
Jeff Doto (research specialist, 2001-2004), went on to MS
Priti Batta (research specialist, 2002-2003), went on to MD
Yelena Bernstein (research specialist, 2002-2004), went on to pharm degree
David Raizen (postdoc, 2002-2007), Asst Professor, UPenn
Craig Stone (grad student, 2002-2008), Medical writer, EBSCO publishing
Kelly Kraus (research specialist, 2003-2004), went on to VMD
Kelly Howell (grad student, 2003-2010), Postdoc, Columbia U.
Olena Vatamaniuk (postdoc, 2004-2005), Assoc Professor, Cornell U.
Anne McKnight (research specialist, 2004-2006), went on to MPH
Kevin Cullison (research specialist, 2004-2008), went on to MD
Vincent Mancuso (grad student, 2004-2011), homemaker
Ariel Junio (research specialist, 2005-2006), went on to industry
Ishmail Abdus-Saboor (grad student, 2006-2012), Postdoc, Weill Cornell Med
Kate Palozola (research specialist, 2009-2011), PhD student, UPenn
Brian Gantick (research specialist, 2010-2011), went on to business
Jean Parry (postdoctoral fellow, 2010-2014), Asst Professor, Georgian Court U.
Jennifer Cohen (research specialist, 2012-2014), PhD student, UPenn
Jesus Ayala-Figuerosa (post-baccalaureate student, 2013-2014), Masters student UPR
Michelle Kanther (postdoctoral fellow, 2013-2014), research specialist, UPenn
and numerous undergraduates, not listed
Parry, J. M.,Sundaram, M. V.: A cell non-autonomous role for Ras signaling in C. elegans neuroblast delamination. Development 141: 4279-4284, Nov 2014.
Sundaram, M.V.: Canonical RTK-Ras-ERK signaling and related alternative pathways. Wormbook. www.wormbook.org, 2013.
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, Stone CE, Murray JI, Sundaram MV: The Nkx5/HMX homeodomain protein MLS-2 is required for proper tube cell shape in the C. elegans excretory system. Dev Biol 366(2): 298-307, June 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.
Howell, K., Arur, S., Schedl, T. and Sundaram, M. V.: EOR-2 is an obligate binding partner of the BTB-Zinc Finger protein EOR-1 in Caenorhabditis elegans. Genetics 184: 899-913, April 2010.
Stone, C. E., Hall, D. H., and Sundaram, M. V.: Lipocalin signaling controls unicellular tube development in the Caenorhabditis elegans excretory system. Developmental Biology 329: 201-211, 2009.
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Last updated: 12/01/2014
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