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Meera V. Sundaram, Ph.D

Meera V. Sundaram, Ph.D

faculty photo
Associate Professor of Genetics
Department: Genetics
Graduate Group Affiliations

Contact information
446A Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
Office: 215-573-4527
Fax: 215-573-5892
Education:
B.A. (Biology)
Mount Holyoke College, magna cum laude , 1986.
Ph.D. (Molecular Biology)
Princeton University, 1993.
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Description of Research Expertise

Research Interests
Tube development and maintenance in C. elegans

Key words: C. elegans, signaling, genetics, cell biology, 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 narrow 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 narrow tubes. C. elegans has many advantages for such studies, including a very simple and well described anatomy that can be visualized by live imaging and that allows phenotypic analysis at single-cell 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 narrow tubes. Some of the questions we're addressing are:

How does auto-fusion promote tube growth and shaping?
We showed that EGF-Ras-ERK signaling controls many aspects of duct tube morphology through a key target, the transmembrane fusogen AFF-1. AFF-1 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 narrow tubes? What is the lipid connection?
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 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. Some of these tube defects can be fixed by changes in EGF signaling or loss of a putative lipid transporter. Current studies are examining links between lipids and apical matrix organization, and probing effects of apical matrix on the cytoskeleton and signaling.

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.

Rotation Projects
1. Conduct a genetic screen for suppressors that "fix" a lethal tube defect, or conduct a dietary supplement screen to identify metabolic factors that improve or exascerbate tube defects
2. Use confocal microscopy to analyze phenotypes and use whole genome sequencing to identify causative variants for an existing mutant of interest
3. Test involvement of a candidate gene by generating new mutant alleles using CRISPR/Cas9 and examining protein localization using GFP reporters

Lab personnel:
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)
Senait Bekele (undergraduate assistant, 2014-present)

Lab alumni:
Robyn Howard-Barfield (grad student 1999-2004), now Group Leader at Catalent Pharma
Craig Stone (grad student 2003-2008), now Medical writer, EBSCO
Kelly Howell (grad student 2004-2010), now postdoc at Columbia U.
Vincent Mancuso (grad student 2006-2011), now homemaker
Ishmail Abdus-Saboor (grad student 2007-2012), now postdoc at UPenn
Ranjana Kishore (postdoc 1998-2002), now Staff Scientist at Caltech
Gautam Kao (postdoc 1999-2003), now Researcher at Gothenburg U. (Sweden)
Kyunghee Koh (postdoc 2001-2003), now faculty at Jefferson U.
Chris Rocheleau (postdoc 2000-2005), now faculty at McGill U.
David Raizen (postdoc 2001-2007), now faculty at UPenn
Olena Vatamaniuk (postdoc 2004-2005), now faculty at Cornell U.
Jean Parry (postdoc 2010-2014), now faculty at Georgian U.

Selected Publications

Meera V. Sundaram and Matthew Buechner: The Caenorhabditis elegans excretory system: a model for tubulogenesis, cell fate specification and plasticity. Genetics 203: 35-63, May 2016.

Hasreet K. Gill*, Jennifer D. Cohen*, Jesus Ayala-Figueroa, Rachel Forman-Rubinsky, Corey Poggioli, Kevin Bickard, Jean M. Parry, Pu Pu, David H. Hall and Meera V. Sundaram : Integrity of narrow epithelial tubes in the C. elegans excretory system requires a transient luminal matrix PLoS Genetics 12(8): e1006205, August 2016.

Meera V. Sundaram and Jennifer D. Cohen: Time to make the doughnuts: Building and shaping seamless tubes. Seminars in Cell and Developmental Biology in press, 2016.

Fabien Soulavie and Meera V. Sundaram: Auto-fusion and the shaping of neurons and tubes. Seminars in Cell and Developmental Biology in press, 2016.

Parry, J. M. and Sundaram, M. V.: A cell non-autonomous role for Ras signaling in C. elegans neuroblast delamination. Development 141: 4279-4284, Nov 2014.

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.

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: 09/28/2016
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