Andrew D. Chisholm
Professor
Sections of Cell and Developmental Biology and Neurobiology, UCSD
e-mail: chisholm@ucsd.edu
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). Ephrin signaling acts 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 (Woo et al., 2004). 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 have 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 (Woo et al., 2008) as essential for elongation and later tissue adhesion. We are exploiting these genetic models to identify additional components of the ECM and cell matrix adhesions.
Epidermal wound healing responses
In animals the epidermis forms a 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 (Tong et al., 2009). We are currently seeking to understand how the epidermis senses damage and how this is transduced to a transcriptional response.
A model for axon regeneration in C. elegans
In collaboration with Yishi Jin (UCSD) we are also studying the ability of C. elegans axons to regrow after laser axotomy (Wu et al., 2007). C. elegans neurons display robust regenerative responses that critically depend on the DLK-1 MAP kinase cascade (Yan et al., 2009). We also find that second messenger cascades are rate limiting in regrowth (Ghosh-Roy et al., 2010). We are currently performing large scale screens to identify novel genes involved in regeneration; interestingly, several genes identified by vritue of their role in epidermal morphogenesis also influence axon 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.
Woo, W.-M., Goncharov, A., Jin, Y., and Chisholm, A.D. 2004. Intermediate filaments are required for C. elegans epidermal elongation. Developmental Biology 267: 216-229.
Chisholm, A.D., and Hardin, J.D. 2005. Chapter on “Epidermal Morphogenesis” for Wormbook (www.wormbook.org).
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. Curr. Biol. 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 106: 1457-1461.
Yan, D., Wu, Z., Chisholm, A.D., Jin, Y. 2009. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell, 138: 1005-1018.
Ghosh-Roy, A., Wu, Z., Goncharov, A., Jin, Y., Chisholm, A.D. 2010. Calcium and cyclic AMP pathways promote axonal regeneration in C. elegans and require DLK-1 kinase. J. Neurosci., in press.
Ghosh-Roy, A. and Chisholm, A.D. 2010. C. elegans: a new model organism for studies of axonal regeneration. Dev. Dynamics, 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.