Ephrin signaling, neuronal development and regeneration in C. elegans
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. Part of our research concerns C. elegans epidermal development and wound healing. We are also studying the roles of the same pathways in neuronal development and regeneration. 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 in epidermal morphogenesis. Ephrin signaling is required for concerted movements of ventral neuroblasts that later form a substrate for epidermal enclosure movements. We use a combination of genetics, laser microsurgery and timelapse microscopy to define the cellular basis of these embryonic 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 are analyzing axonal outgrowth and guidance events that may specifically require ephrin reverse signaling. 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 neuronal development In screens for epidermal morphogenesis defects we have identified several novel components of the extracellular matrix. As well as being essential for normal epidermal morphogenesis, we find that these play important roles in the development and maintenance of neural architecture. We are analyzing two molecules in depth, the ECM protein F-spondin and the extracellular peroxidase peroxidasin. Axonal regeneration in C. elegans
Using femtosecond laser surgery we also showed that C. elegans neurons regenerate following damage. In collaboration with Y. Jin (UCSD) we have developed C. elegans as a simple model for aspects of neuronal regeneration following injury. We are currently defining the roles of trafficking and signaling pathways in regrowth.
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., 194: 352-365. 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. Chin-Sang, I.D., S L. Moseley, M. Ding, R.J. Harrington, S.E. George, and Chisholm, A.D. 2002. The divergent C. elegans ephrin EFN-4 functions in embryonic morphogenesis in a pathway independent of the VAB-1 Eph receptor. Development 129: 5499-5510