Research Specialties: Developmental Cell Biology, cell architecture, tissue morphogenesis, extracellular matrix
A fundamental question facing developmental biologists and tissue engineers is: How do epithelial cells form the uniquely shaped structures (e.g. flat sheets, spherical cysts, elongated tubes) that are critical for tissue function? It is known that the architecture of virtually all epithelia is dependent upon coordinated adhesive interactions between individual cells and extracellular substrates. These interactions are mediated by transmembrane receptors that are linked to the cytoskeleton by cytoplasmic adapter proteins. Defective interactions between epithelial cells and their extracellular substrates are implicated in a wide variety of pathological conditions that include tissue fragility diseases and increased tumor invasiveness.
My laboratory is interested in the regulation of epithelial morphogenesis during development, with a specific interest in how extracellular matrix proteins, transmembrane receptors, and cytoskeletal adapters work together to specify tissue architecture. Although little is known about specific mechanisms that regulate epithelial cell morphology, these mechanisms are conserved between species and involve the localized deposition of molecules that contain adhesive and/or positional information. We have chosen a genetic approach, using screens to identify C. elegans mutants with defects in genes controlling epithelial differentiation. To date, we have identified and characterized hemicentin, an extracellular matrix protein with a modular structure (figure 1) that is involved in the differentiation of specialized epithelial cells in C. elegans and has 2 highly conserved orthologs in the human genome.
Where is hemicentin expressed?
We have constructed a functional fusion between hemicentin and green fluorescent protein (GFP), enabling us to monitor hemicentin-GFP localization in live animals during development. Hemicentin accumulates at sites where epithelial cells make long, line-shaped attachments to a number of tissues including specific uterine cells and subsets of neurons, including those involved in mechanosensation (figure 2).
Our current focus is on using molecular, genetic and biochemical techniques to identify the functional significance of hemicentin structural domains and on identifying cell surface receptors and other extracellular proteins that functionally interact with hemicentin.
The long-term goal is to understand the function of extracellular matrix proteins in the modification of epithelial cell architecture. Specific questions that we plan to address include: What are the roles of vertebrate hemicentins? How can hemicentin be used in the design of bioactive synthetic matrices to regulate the morphogenesis of engineered tissues?
Research Images:Figure 1. Schematic of hemicentin structure. Unique, but highly conserved N and C terminii flank 48 tandem Ig and 3 EGF modules.
Figure 2. Hemicentin-GFP assembles into polymers on the surface of neurons (A,B), between head muscles and pharynx (C), and in the ovary (D).
Lab Techniques and Equipment:
Vogel, BE and Hedgecock, EM. (2001) Hemicentin, a conserved extracellular member of the immunoglobulin superfamily, organizes epithelial and other cell attachments into oriented line-shaped junctions. Development 128:883-894.
Muriel, JM, Dong, C, Hutter, H and Vogel, BE. (2005) Fibulin-1C and Fibulin-1D splice variants have distinct functions in C. elegans development and assemble in a hemicentin dependent manner. Development 132:4223-4234.
Dong, C, Muriel, JM, Ramirez, S, Hutter, H, Hedgecock, EM, Breydo, L, Baskakov, IV and Vogel, BE (2006) Hemicentin assembly in the extracellular matrix is mediated by distinct structural modules. J. Biol. Chem. 281:23606-23610.
Muriel, JM, Xu, X and Vogel, BE. (2006) Selective assembly of fibulin-1 splice variants reveals distinct extracellular matrix networks and novel functions for Perlecan/UNC-52 splice variants. Dev. Dyn. 235:2632-40.
Vogel BE, Muriel JM, Dong C, Xu X. (2006) Hemicentins: what have we learned from worms? Cell Res. 16:872-8.
Xu X, Dong C, Vogel BE. (2007) Hemicentins assemble on diverse epithelia in the mouse. J Histochem Cytochem. 55:119-26.
Xu X and Vogel BE. (2011) A secreted protein promotes cleavage furrow maturation during cytokinesis. Curr Biol. 21:114-9. PMCID: PMC3046554
Vogel BE, Wagner C, Paterson JM, Xu X, Yanowitz JL. (2011) An extracellular matrix protein prevents cytokinesis failure and aneuploidy in the C. elegans germline. Cell Cycle. Jun 15;10(12):1916-20. Epub 2011 Jun 15. PMCID: PMC3154414
Xu X, Vogel BE. (2011) A new job for ancient extracellular matrix proteins: Hemicentins stabilize cleavage furrows. Commun Integr Biol. Jul; 4(4):433-5. doi: 10.4161/cib.4.4.15324. Epub 2011 Jul 1. PMCID: PMC3181513
Muriel JM, Dong C, Vogel BE. (2012) Distinct regions within fibulin-1D modulate interactions with hemicentin. Exp Cell Res. 2012 Dec 10; 318 (20) : 2543-7. doi: 10.1016/j.yexcr.2012.08.007. Epub 2012 Sep 7.
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