|Dominique R. Alfandari
Assistant Professor of Veterinary and Animal Science, University of Massachusetts
Ph.D.: University of Pierre & Marie Curie, Paris 6 (France)
ADAM metalloprotease function during embryonic Development
ADAMs are cell-surface-Metalloproteases that contain a Disintegrin domain. They were initially discovered on the surface of mature spermatozoid where they play a role during fertilization. The domain organization of ADAM proteins is related to snake venom metalloproteases. When these venoms are released into a victim, the metalloprotease domain degrades the walls of blood vessels while the disintegrin domain prevents platelet integrins from binding and forming blood clots. The combination of these 2 functions induces hemorrhages that can lead to the death of the victim. My group is interested in cell movements that shape the vertebrate embryo. More precisely we are interested in cell interactions either with other cells or with the extracellular environment that control cell movements. We have chosen the Frog embryo (Xenopus Laevis) to study these phenomena because of the large number of embryos that can be generated (thousandths per female), the wide array of molecular reagents available for this specie and the amount of knowledge accumulated over the years by classical embryologists.
Our current research is centered on the function of the ADAM13 metalloprotease during cranial neural crest cell migration. Cranial neural crest are cells that originate at the lateral edge of the anterior neural plate and migrate toward the ventral side of the embryo to colonize the head and make most of the facial cartilages, muscle and bones of the face. These cells are present in all vertebrates including humans. We have shown that if ADAM13 function is prevented, cranial neural crest cells do not migrate into their normal migration pathways. We also showed that ADAM13 binds, cleaves and remodels a substrate composed of the extracellular matrix protein fibronectin. Our current model is that ADAM13 function is to modify the cranial neural crest cell pathways to promote migration of subpopulation of cells in the correct paths.
Our multiple interests in cell behaviors during embryogenesis are reflected by our wide array of techniques. We use Molecular Biology to clone, mutate, express or knock-out genes that we want to study. Biochemical analyzes to identify protein complexes, proteolytic substrates and post-transcriptional regulation of selected proteins in the embryos. Finally we use grafts, live labeling and imaging of cells in whole embryos as well as in vitro cultured explants to understand detail cellular behavior in response to various conditions.
Alfandari, D. (2005). ADAM13 function in development: Prototypical or unique ADAM? In "The ADAM Familly of Proteases" (H. a. Lendeckel, Ed.), Vol. Chapter 7. Kluwer plenum.
DeSimone, D. W., Davidson, L., Marsden, M., and Alfandari, D. (2004). The Xenopus embryo as a Model System for studies of Cell Migration. In ""Cell Migration in Development" Methods in Molecular Biology" (G. J.L., Ed.), pp. in press. Humana Press, Totawa, NJ.
Cousin, H., and Alfandari, D. (2003). A PTP-PEST like protein affects (alpha)5(Beta)1 integrin-dependent matrix assembly cell adhesion and migration in xenopus gastrula. Dev Biol in press.
Alfandari D., Cousin H., Gaultier A.,Hoffstrom B.G., and DeSimone D.W. 2003. Integrin ???? supports the migration of Xenopus Cranial Neural Crest on fibronectin. Dev.Biol . 260, 2, 449-64.
Gaultier A., Cousin H., Darribère T. and Alfandari D. 2002. ADAM13 disintegrin and cysteine-rich domains bind to the Hep II domain of fibronectin. J. Biol. Chem. 277, 26, 23336-23344.
Alfandari D., Cousin H., Gaultier A., Smith KM., White JM., Darribere T., and DeSimone DW. 2001. Xenopus ADAM13 is a metalloprotease required for cranial neural crest cell migration. Current Biology. 11, 918-930.
Cousin H., Gaultier A., Bleux C., Darribère T. and Alfandari D. 2000. X-PACSIN2 is a regulator of the Metalloprotease/Disintegrin ADAM13. Dev. Biol. 227, 197-210.
Alfandari D., Wolfsberg T.G., White J.M. and DeSimone D.W. 1997. ADAM 13: A Novel ADAM Expressed in Somitic Mesoderm and Neural Crest Cells during Xenopus laevis Development. Dev. Biol. 182, 314-330.