Michael G. Rosenfeld
Adjunct Professor of Biology, UCSD, Professor of Medicine
Investigator, Howard Hughes Medical Institute

e-mail: mrosenfeld@ucsd.edu

     Our laboratory investigates the molecular mechanisms by which several classes of transcription factors, including nuclear receptors, POU domain and homeodomain factors, alter gene expression and orchestrate organ development of the mammalian neuroendocrine and neural systems. These systems that serve in complex organisms to coordinate molecular signalling between cells and organs in response to diverse signal transduction pathways. Our investigations have provided insight into the underlying molecular strategies of regulated transcription and of organogenesis. The emergence of specific cell types from a common primordium, identifying a series of novel determining factors that coordinate the appearance of specific cell phenotypes, and novel mechanisms of positive and negative transcriptional regulation of gene expression. 

     A description of our findings in pituitary development is provided as an example of our research program. The pituitary gland and a specific brain area, the endocrine hypothalamus, coordinately developed to generate the hypothalamic-pituitary axis, required for physiological homeostasis and survival, with specific hormone-producing cell types emerging in a spatially- and temporally-specific fashion from an ectodermal primordium. We have provided in vivo and in vitro evidence that pituitary development involves three sequential phases of signaling events and the action of a gradient at an ectodermal boundary. In the first phase, the BMP4 signal from the ventral diencephalon, expressing BMP4, Wnt5a, and FGF8, represents a critical dorsal neuroepithelial signal for pituitary organ commitment in vivo. In the second phase, a BMP2 signal emanates from a ventral pituitary organizing center that forms at the boundary of a region of oral ectoderm in which Shh expression is selectively excluded. Opposing BMP2 and FGF8 activity appears to generate overlapping patterns of specific transcription factors underlying cell lineage specification events. Finally, temporally specific loss of the BMP2 signal is required to allow terminal differentiation.  The consequence of these sequential organ and cellular determination events is that each of the hormone-producing pituitary cell types appear to be determined in a ventral-to-dorsal gradient, respectively. We identified a tissue-specific POU domain transcription factor, Pit-1, that is required for differentiation of three pituitary cell types and identified target genes, including trophic factor receptors required for proliferation of specific cell types, and solving two genetic diseases caused by these regulatory molecules. 

     We have identified novel co-activators and co-repressors (NCoR) for the nuclear receptors and for other classes of transcription factor, and showed that ligand-dependent transcriptional activation involves an exchange of an NCoR corepressor complex containing histone deacetylase activates for a coactivator complex containing histone acetyltransferase; the properties of the novel factors have led to a model of nuclear integration of distinct signal transduction pathways. 

     We are currently applying genetic, biochemical, and molecular biological approaches to understand precisely the molecular mechanisms that control gene transcription, and their modulation, by signal transduction pathways during organogenesis. 

      Treier, M., Gleiberman, A.S., O'Connell, S.M., Szeto, D.P., McMahon, J.A., McMahon, A.P. and Rosenfeld, M.G. (1998). Multistep Signaling Requirements for Pituitary Organogenesis In Vivo. Genes & Dev.12:1691-1704. 

      Korzus E., Torchia, J., Rose, D.W., Xu, L., Kurokawa, R., McInerney, E.M., Mullen, T.M., Glass, C.K. and Rosenfeld, M.G. (1998). Transcription factor-specific requirements for coactivators and their acetyltransferase functions. Science 279:703-707. 

      Heinzel, T., Lavinsky, R.M., Mullen, T.M., Söderström, M., Laherty, C.D, Torchia, J., Yang, W-M, Brard, G., Ngo, S.D., Davie, J.R., Seto, E., Eisenman, R.N., Rose, D.W., Glass, C.K. and Rosenfeld, M.G. (1997). A complex containing N-Cor, mSin3, and histone deacetylases mediates transcriptional repression. Nature 376:43-48. 

      Torchia, J., Rose, D.W., Inostroza, J., Kamei, Y., Westin, S., Glass, C.K. and Rosenfeld, M.G. (1997). The transcriptional coactivator, p/CIP, binds CBP and mediates nuclear-receptor function. Nature 387: 677-684. 

      Sornson, M.W., Wu, W., Dasen, J.S., Flynn, S., Norman, D.J., O'Connell, S.M., Gukovsky, I., Carrière, C., Ryan, A.K., Miller, A.P., Zuo, L., Gleiberman, A.S., Andersen, B., Beamer, W.G. and Rosenfeld, M.G. (1996). Pituitary lineage determination by the Prop-1 homeodomain factor defective in Ames dwarfism. Nature 384:327-333. 

Geof Rosenfeld received his degrees from the John Hopkins University and from the University of Rochester and performed postdoctoral training at the National Institutes of Health and Washington University. Dr. Rosenfeld has been an Investigator with the Howard Hughes Medical Institute since 1985. He has received a McKnight Award and the Ernst Oppenheimer Young Investigator Award, and was elected to the American Academy of Arts and Sciences.