Tubes are the building blocks of most human organs. Defects in tube development cause serious birth defects, while defects in tube maintenance underlie many common health problems such as kidney disease, heart disease and stroke. It is therefore important to understand how tubes initially form and are maintained. Unicellular tubes are a special class of very tiny tubes, just one cell in diameter. Mammals have many such tubes in the capillary beds that interface with organs such as the brain and kidney. Unicellular tubes also appear to be precursors to larger bore tubes in the vasculature. Despite this, very little is known about how unicellular tubes develop in vivo or to what degree they rely on the same polarity pathways as more complex multicellular tubes. We will identify molecular requirements for unicellular tube development and maintenance in the C. elegans excretory system, a simple renal-like organ consisting of only 3 unicellular tube cells. We've identified the EGF-Ras-ERK pathway and multiple other genes as important for tube development or maintenance in this organ. We will use these and other existing mutants to gain insight into two main questions.
Aim 1) What establishes "apical inward" polarity and controls where epithelial junctions form to create a unicellular tube? We will (a) use live imaging to visualize tubulogenesis in WT and various mutants to ask what patterns of cell contact favor unicellular tube development~ (b) Systematically test the requirements for known polarity regulators in unicellular tube development~ and (c) Conduct unbiased genetic screens to find more genes important for unicellular tube development.
Aim 2) Once formed, how are unicellular tube junctions and lumen maintained, and what triggers their disassembly? We will (a) Test the roles of two newly discovered apically-localized transmembrane proteins in apical domain organization~ (b) Test if downregulation of one of these proteins is involved in EMT-like withdrawal~ and (c) Identify additional genes required for tube maintenance. Our experiments take advantage of the system's very simple anatomy and powerful imaging and genetic approaches possible in C. elegans to address central questions about unicellular tubes that are also relevant to the biology of all tubes.

Public Health Relevance

Problems with tube development or maintenance cause birth defects such as spina bifida and many common diseases such as kidney disease, heart disease and stroke. These studies investigate how tubes develop and are maintained, with a special emphasis on the tiniest tubes in our bodies. Understanding these mechanisms will help in the design of therapies to prevent or treat tube-related disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058540-11
Application #
8449297
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2000-04-01
Project End
2015-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
11
Fiscal Year
2013
Total Cost
$324,240
Indirect Cost
$121,590
Name
University of Pennsylvania
Department
Genetics
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Sundaram, Meera V (2013) Canonical RTK-Ras-ERK signaling and related alternative pathways. WormBook :1-38
Mancuso, Vincent P; Parry, Jean M; Storer, Luke et al. (2012) Extracellular leucine-rich repeat proteins are required to organize the apical extracellular matrix and maintain epithelial junction integrity in C. elegans. Development 139:979-90
Abdus-Saboor, Ishmail; Stone, Craig E; Murray, John I et al. (2012) The Nkx5/HMX homeodomain protein MLS-2 is required for proper tube cell shape in the C. elegans excretory system. Dev Biol 366:298-307
Abdus-Saboor, Ishmail; Mancuso, Vincent P; Murray, John I et al. (2011) Notch and Ras promote sequential steps of excretory tube development in C. elegans. Development 138:3545-55
Howell, Kelly; Arur, Swathi; Schedl, Tim et al. (2010) EOR-2 is an obligate binding partner of the BTB-zinc finger protein EOR-1 in Caenorhabditis elegans. Genetics 184:899-913
Stone, Craig E; Hall, David H; Sundaram, Meera V (2009) Lipocalin signaling controls unicellular tube development in the Caenorhabditis elegans excretory system. Dev Biol 329:201-11
Rocheleau, Christian E; Cullison, Kevin; Huang, Kai et al. (2008) The Caenorhabditis elegans ekl (enhancer of ksr-1 lethality) genes include putative components of a germline small RNA pathway. Genetics 178:1431-43
Raizen, David M; Cullison, Kevin M; Pack, Allan I et al. (2006) A novel gain-of-function mutant of the cyclic GMP-dependent protein kinase egl-4 affects multiple physiological processes in Caenorhabditis elegans. Genetics 173:177-87
Sundaram, Meera V (2006) RTK/Ras/MAPK signaling. WormBook :1-19

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