Raphael Kopan, Ph.D.
Associate Professor of Dermatology and Molecular Biology and Pharmacology
Molecular biology of vertebrate development, Cell fate selection in the skin
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Research
A central process in development of multicellular organisms is the generation of different cell types. One mechanism involved in this process is based on cell-cell interactions between equivalent cells, leading to inhibition of one cell fate in a subset of cells. Remarkably, vertebrate homologs of Notch have been cloned from many organisms and experimental data suggest that a conserved signal transduction pathway is involved in cell fate selection during vertebrate development. My lab is dissecting the biochemical steps involved in the signal transduction by Notch. We demonstrated that Notch signaling is propagated through release of its intracellular domain. We are testing the possibility of additional signaling mechanisms by manipulating mouse embryos to express processing deficient Notch 1. We are now placing genetic modifiers of Notch in this biochemical pathway-genes like Presenilin, Deltex, Numb, Disheveled, Sanpodo and GSK3b are under investigation. We are also interested in identifying downstream target genes. A second focus is to understand the molecular basis of cell fate selection in the hair follicle and the role of the Notch pathway in this process. We use the hair follicle as a model for the study of cell diversity at the tissue level. The vertebrate skin is one tissue that combines many advantages for such a study. It contains several differentiated structures (i.e., hair, epidermis, and glands) which differentiate properly only as a result of mesenchymal-epithelial interactions and responds to hormonal signals. Many known signaling pathway are active in skin differentiation, and most importantly, the skin can tolerate disruption of developmental programs better than other essential tissues; such disruptions can be induced late since hair follicles repeat their developmental program throughout the animal's adult life. We have generated transgenic animals expressing Notch in a single cell type within the follicle and are analyzing its phenotype. Preliminary analysis shows that altering Notch expression effects follicle architecture.