Research Abstract:
A central process in development of multicellular organisms involves generation of different cell types and specialized organs. Remarkably, experimental data suggest that only a small number of conserved signal transduction pathways are involved in generating an enormous diversity of cell types during metazoans organogenesis, and that these pathways work both in development and during adult tissue renewal. The Notch pathway is involved in these processes and is in charge of short-range communicates between equivalent cells, leading to acquisition of a particular fate in a limited subset of cells within the initial group. 4 vertebrate homologs of Drosophila Notch have been identified in mice and humans. My lab demonstrated that Notch signaling is propagated through release of its intracellular domain that acts as a nuclear transcription factor (Huppert et al., 2000; Schroeter et al., 1998). We are testing how "context" impacts Notch signaling by different paralogs and in different cellular milieu using high throughput approaches. Students joining the lab will be involved in characterization of genetic modifiers of Notch identified in these screens.
A second focus of my lab aims to understand the molecular basis of organogenesis. Specifically, we wish to understand how the same signaling pathway produces functionally and morphologically distinct organs. We use the skin and the kidney as model systems for modular organs (i.e, made of multiple identical units) in which to decipher the mechanisms involved in the study of cell diversity at the tissue level. The vertebrate skin and kidney combine many advantages for such a study. The skin 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. The kidney is composed a multitude of nephrons and depends on mesenchymal-epithelial interactions as well. For both organs, many of the critical signaling events have been identified, and similar pathways (but in different order) are deployed during organogenesis. Most importantly, the skin can tolerate disruption of developmental programs in vivo better than other essential tissues whereas the essential kidney can be studied in organ culture. For both systems, gene delivery and knockdown systems are under development or already exist in the lab.
The comparison between these organs indicate that Notch signaling is utilized they utilize Notch at different periods in their history (Cheng et al., 2003; Pan et al., 2004) within the larger signaling network. We now wish to use these organs to address the mechanism that underlie their differences with an initial focus on Notch utilization. We are analyzing targets, interactions with other signaling pathways, and existence of tissue specific modifiers. For other projects, see recent publications (Chandu et al., 2006; Huppert et al., 2005; Lubman et al., 2005; Ong et al., 2006).
Selected Publications:
Cheng HT, Kim M, Valerius MT, Surendran K, Schuster-Gossler K, Gossler A, McMahon AP and Kopan R. Notch2, but not Notch1, is required for proximal fate acquisition in the mammalian nephron. Development 2007 134: 801-811.
Demehri, S., Turkoz, A., and Kopan, R. Epidermal Notch1 Loss Promotes Skin Tumorigenesis by Impacting the Stromal Microenvironment. Cancer Cell 2009 16: 55-66
Demehri S, Liu Z, Lee J, Lin MH, Crosby SD, Roberts CJ, Grigsby PW, Miner JH, Farr AG and Kopan R. Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. PLoS Biol 2008 6, e123.
Demehri S, Morimoto M, Holtzman MJ and Kopan R. Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol 2009 7, e1000067. doi:1000010.1001371/journal.pbio.1000067.
Vooijs M, Ong CT, Hadland B, Huppert S, Liu Z, Korving J, van den Born M, Stappenbeck T, Wu Y, Clevers H, et al. Mapping the consequence of Notch1 proteolysis in vivo with NIP-CRE. Development 2007 134: 535-544.
Last Updated: 08/27/2009 |