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Andrew D. Chisholm e-mail: chisholm@ucsd.edu |
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My lab’s interests are in the early development of epidermal and neuronal tissues, and more recently in the responses of epidermal and neuronal cells to damage. We are studying these processes in the nematode worm Caenorhabditis elegans. C. elegans is an excellent organism for analyzing fundamental aspects of development. Worm genetics is simple and cheap; gene function can also be probed using genome wide RNA interference screens. Embryogenesis takes 12 hours and its dynamics can be studied using timelapse microscopy and fluorescent markers.
We focus on epidermal (skin) development as a model for epithelial morphogenesis. The worm epidermis is a simple epithelium that surrounds the animal. In embryogenesis the epidermis spreads out over substrate cells to enclose the embryo (enclosure) and subsequently undergoes elongation (Chisholm and Hardin 2005). Pathways involved in these processes are evolutionarily conserved, and several are implicated in cancer or other genetic diseases.
Eph Signaling and the role of the neuronal substrate in epidermal enclosure
We showed that signaling via the C. elegans Eph receptor tyrosine kinase and its ephrin ligands are required for enclosure (Chin-Sang et al., 1999). The role of ephrin signaling is to promote earlier movements of neuroblasts that form a substrate for epidermal enclosure. We are currently using genetics, laser microsurgery and quantitative timelapse microscopy to define the cellular and molecular basis of these neuroblast migrations. The role of Eph signaling is especially interesting as it involves both forward (receptor kinase dependent) and reverse (ephrin-dependent) signals. We are studying this process to learn how GPI-linked ephrins signal.
Cell-matrix interactions in epidermal cell shape change
We discovered that the epidermal intermediate filament cytoskeleton plays an essential role in elongation. Intermediate filaments (IFs) play a multitude of roles in animal cells, and are mutated in numerous human diseases. In C. elegans we showed that they promote epidermal cell strength and are essential for cell shape changes in elongation. We identified new components of IF-coupled cell-matrix attachments (VAB-19, EPS-8) that may play roles in communication between cell matrix attachments and the actin cytoskeleton. We have also identified components of the extracellular matrix (F-spondin, Peroxidasin; Woo et al., 2008) as essential for elongation. These findings emphasize the importance of the extracellular matrix and cell-matrix junctions in organogenesis.
Epidermal wound healing responses
In all animals the epidermis forms the first line of defense against injury and microbial pathogens. In collaboration with Jonathan Ewbank (Marseille) we have developed C. elegans as a model for epidermal wound responses (Pujol et al., 2008). We have identified mutants in which the epidermal damage response is constitutively activated and are studying these to identify new components of the damage response (Tong et al., in press).
A model for axon regeneration in C. elegans
In collaboration with Yishi Jin (UCSD) we are also studying the response of neurons to laser axotomy (Wu et al., 2007). C. elegans neurons display robust regenerative responses that we find are under the control of both intrinsic and extrinsic factors. We are currently performing large scale screens to identify novel genes involved in regeneration.
Chin-Sang, I., George, S.E., Ding, M., Moseley, S.L., Lynch, A.S., and Chisholm, A.D. 1999. The Ephrin VAB-2/EFN-1 Functions in Neuronal Signaling to Regulate Epidermal Morphogenesis in C. elegans. Cell 99:781-790.
Chisholm, A.D., and Hardin, J.D. 2005. Chapter on “Epidermal Morphogenesis” for Wormbook (www.wormbook.org).
Hudson, M.L., Kinnunen, T., Cinar, H.N. and Chisholm, A.D. 2006. C. elegans Kallmann syndrome protein KAL1 interacts with syndecan and glypican to regulate neuronal cell migrations. Dev. Biol. 194:352-365.
Wu, Z., Ghosh-Roy, A., Yanik, M.F., Zhang, J.Z., Jin, Y., and Chisholm, A.D. 2007. C. elegans neuronal regeneration is influenced by life stage, synaptic branching, and ephrin signaling. Proc. Natl. Acad. Sci. USA 104:15132-15137.
Pujol, N., Cypowyj, S., Ziegler, K., Millet, K., Astrain, A., Goncharov, A., Jin, Y., Chisholm, A.D., and Ewbank, J.J. 2008. Distinct innate immune responses to infection and wounding in the C. elegans epidermis. Current Biology 18:481-489.
Woo, W.-M., Berry, E.C., Hudson, M.L., Swale, R., Goncharov, A., Jin, Y., Chisholm, A.D. 2008. The C. elegans F-spondin family protein SPON-1 maintains adhesion in neural and non-neural tissues. Development 135:2747-2756.
Tong, A., Lynn, G., Ngo, V., Wong, D., Moseley, S.L., Ewbank., J.J., Goncharov, A., Wu, Y., Pujol, N., and Chisholm, A.D. Negative regulation of C. elegans epidermal damage responses by Death Associated Protein Kinase. Proc. Natl. Acad. Sci. USA, in press.
Andrew Chisholm received his Ph.D. in 1989 from Cambridge University, England, working at the Medical Research Council Laboratory of Molecular Biology. He conducted postdoctoral research with H. Robert Horvitz at the Massachusetts Institute of Technology. From 1996 to 2006 he was on the faculty of the University of California, Santa Cruz.
