Tubular organ development in C. elegans
C. elegans, signal transduction, Ras, genetics, tube development.
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. Defects in these tiny tubes are associated with cardiovascular diseases, stroke and age-associated dementia.
My lab's research utilizes the “excretory” or renal-like system of the nematode worm Caenorhabditis elegans as a model system for studying the mechanisms that build, shape and stabilize unicellular tubes. 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 – an important feature when studying unicellular tubes! C. elegans also is highly amenable to powerful forward and reverse genetic approaches to find genes involved in a process of interest. Using forward genetic screens, our lab has identified many genes that are important for building, shaping and stabilizing unicellular tubes. Some of the questions we're addressing are:
How does EGF-Ras-ERK signaling promote tube growth and shaping?
Receptor tyrosine kinase signaling controls tube identity and morphogenesis in most organ systems. We showed that EGF-Ras-ERK signaling promotes excretory duct tube identity and subsequent tube elongation. One key downstream target of signaling is the transmembrane fusogen AFF-1, which fuses duct cell plasma membranes to convert an autocellular "seamed" tube into a "seamless" tube that lacks adherens junctions or tight junctions along its length. We are studying this role of AFF-1 and other cytoskeletal changes and vesicle trafficking pathways that allow the duct to grow and take on its distinctive elongated shape.
How does the luminal extracellular matrix shape and protect unicellular tubes?
Most tubes secrete various glycoproteins 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 transmembrane or secreted proteins that are required to shape and protect the narrow duct and pore tubes, and to maintain junction connectivity. These include zona pellucida (ZP) domain proteins, extracellular leucine-rich repeat only (eLRRon) proteins, and lipocalins ("cups of fat"). Current studies are examining links among the luminal matrix, cytoskeleton and signaling pathways.
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.
1. Conduct a genetic screen for suppressors that "fix" a lethal mutant defect or enhancers that worsen it
2. Use whole genome sequencing to identify molecular variants associated with a mutant defect (or suppressor)
3. Test involvement of a candidate gene by analyzing mutant phenotypes using confocal microscopy of living specimens
Jennifer Cohen (graduate student, 2015-present)
Emily Pu (postdoctoral fellow, 2012-present)
Fabien Soulavie (postdoctoral fellow, 2013-present)
Rachel Forman-Rubinsky (research specialist, 2014-present)
Hasreet Gill (research specialist, 2014-present)
Senait Bekele (undergraduate assistant, 2014-present)
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: 05/23/2016
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