Andrew D. Chisholm Professor of Biology, UCSD e-mail: chisholm@ucsd.edu

       My lab is interested in morphogenesis of cell, tissues, and organs.  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.  The worm genome is compact and has been fully sequenced and annotated.  Embryonic development takes 12 hours and its dynamics can be studied using timelapse microscopy and fluorescent markers.

       Our studies have recently focused 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 undergoes coordinated spreading movements known as enclosure.  The epidermis actively spreads over substrate neurons that we have found to play important roles in the spreading process.  The epidermis then undergoes elongation, coordinated cell shape changes that squeeze the embryo from a bean shape to a long thin worm.  Using genetics we identified molecules that play key roles in these morphogenetic processes.  All the genes discovered in these studies are conserved in evolution, and several are implicated in human diseases.  Our studies provide tractable genetic models for these conserved gene families.

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 normal enclosure movements of the epidermis. The role of ephrin signaling is to promote earlier movements of neuroblasts that set up the substrate for epidermal enclosure.  We are currently using a combination of genetics, laser microsurgery and timelapse microscopy to define the cellular 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.  We have also defined several other pathways (LAR receptor phosphatase, Kallmann syndrome protein) that act in parallel to Eph signaling.  We are currently exploiting this genetic redundancy in enhancer screens to identify new components of these pathways.

Cell-matrix interactions in epidermal cell shape change
       We are also interested in a dramatic morphogenetic process in later embryogenesis known as elongation.  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.  Using genetics we have also identified components of the extracellular matrix (F-spondin, Peroxidasin) as essential for elongation.  These studies emphasize the importance of cell-cell interactions in the morphogenesis of organs.

Epidermal wound healing and nerve regeneration in C. elegans
       In later life the epidermis is the first line of defense of the worm against physical injury and environmental pathogens.  We are studying the response of the epidermis to damage by needle and laser wounding.  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.  Using femtosecond laser surgery we also showed that C. elegans neurons regenerate following damage.  In collaboration with Y. Jin (UCSD) and M.F. Yanik (MIT) we are defining molecules involved in neuronal regeneration.

        Wu Z, Ghosh-Roy A, Yanik MF, Zhang JZ, Jin Y, Chisholm AD. (2007).   Caenorhabditis elegans neuronal regeneration is influenced by life stage, ephrin signaling, and synaptic branching. Proc Natl Acad Sci U S A. 104(38):| 15132-15137.

        Hudson, M.L., Kinnunen, T., Cinar, H.N. and Chisholm, A.D. (2006). C. elegans Kallmann syndrome protein KAL‑1 interacts with syndecan and glypican to regulate neuronal cell migrations.  Dev. Biol. 294: 352-365.

       Chisholm, A.D. and Hardin, J.  (2005).  Chapter on “Epidermal Morphogenesis” for Wormbook (www.wormbook.org) (review)

       Yanik, M.F., Cinar, H., Cinar, H.N., Chisholm, A.D., Jin, Y., and Ben-Yakar, A.  (2004).  Neurosurgery: functional regeneration after laser axotomy. Nature 432: 822.

       Ding, M., Goncharov, A., Jin, Y., Chisholm, A.D.  (2003).  C. elegans ankyrin repeat protein VAB‑19 is a component of epidermal attachment structures and is essential for epidermal morphogenesis.  Development 130: 5791-5801.

       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.

       George, S.E., Simokat, K., Hardin, J., and Chisholm, A.D.  (1998).  The VAB‑1 Eph Receptor Tyrosine Kinase Functions in Neural and Epithelial Morphogenesis in C. elegans.  Cell 92: 633-643.

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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.