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.
Ras signaling, Notch signaling and cell fate specification
Both the EGFR/Ras/ERK and Notch signaling pathways play important roles in specifying excretory system cell fates. These pathways also are used to control many other developmental events, and a major question concerns the downstream targets of these pathways, how cell-type appropriate targets are chosen, and how these targets act with other cell intrinsic factors to elicit specific responses. The lab has identified and is characterizing a number of potential ERK targets important for excretory duct cell fate specification, as well as scaffold proteins that modulate signaling in a cell-type specific manner.
Lipocalin signaling and tubular morphogenesis
The tubular cells of the excretory system are an excellent model for studying mechanisms of intracellular lumen formation and tube connectivity. Through genetic screening, we discovered a lipocalin-dependent signaling mechanism that controls lumen connectivity. Lipocalins are secreted cup-shaped proteins that bind sterols, odorants and other small lipophilic molecules and deliver them to target cells via specific plasma-membrane bound receptors. Studies are underway to identify the signaling pathway and cellular mechanism through which the LPR-1 lipocalin is acting. These studies are likely to be relevant to development of capillaries in the mammalian microvasculature, which are also networks of single-celled tubes.
Epithelial junction integrity and remodeling
The tubular cells of the excretory system are also an excellent model for studying junction formation and remodeling. These cells undergo de novo epithelialization and junction formation during tubulogenesis, and the excretory pore cell later undergoes a programmed withdrawal and loss of epithelial identity. We identified a family of apically localized transmembrane "eLRRon" proteins that are required to organize the apical extracellular matrix and maintain junction connectivity. Current studies are examining the link between matrix and junctions, and testing whether modulation of eLRRon activity contributes to programmed junction remodeling.
Please see Meera about possible projects
Gregory Osborn, graduate student (jointly supervised with John Murray)
Michelle Kanther, postdoctoral fellow
Jean Parry, postdoctoral fellow
Emily Pu, postdoctoral fellow
Jennifer Cohen, research specialist
Hasreet Gill, undergraduate assistant
Julian Bello, undergraduate assistant
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.
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.
Rocheleau, C. R., Cullison, K., Huang, K., Bernstein, Y., Spilker, A. C. and Sundaram, M. V.: The Caenorhabditis elegans ekl (enhancer of ksr-1 lethality) genes include putative components of a germline small RNA pathway. Genetics 178: 1431-1443, 2008.
Rocheleau CE., Ronnlund A., Tuck S., Sundaram MV.: Caenorhabditis elegans CNK-1 promotes Raf activation but is not essential for Ras/Raf signaling. Proceedings of the National Academy of Sciences of the United States of America 102(33): 11757-62, Aug 16 2005.
Sundaram, M. V. : RTK/Ras/MAPK signaling in C. elegans. Wormbook http://www.wormbook.org. edited by the Community of C. elegans Researchers (eds.). 2005.
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Last updated: 05/29/2013
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