Our laboratory investigates the molecular mechanisms by which several classes of transcription factors, including nuclear receptors, POU domain and homeodomain factors, orchestrate development of the specific neuro for mammalian central neuro systems as well as neuroendocrine systems. These systems 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 organogenesis, and 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 fundamental aspect of the development of complex organ systems is a requirement for precise temporal and spatial coordination in the genesis of tissues of distinct embryonic origins in order to form functional units required for physiological homeostasis and survival. Such a requirement is particularly well exemplified in mammalian development by the formation of CNS and endocrine system. For example, the generation of the hypothalamic-pituitary axis, which exhibits a remarkable degree of developmental coordination, such that the initial activation of peptide expression by neurosecretory neurons is virtually coincident with the arrival of their axonal projections at the median eminence or the posterior pituitary, and the initial appearance of specific receptors for these regulatory neuropeptides. This neuroendocrine system integrates signals from the periphery and brain to modulate production and secretion of regulatory hormones by specific pituitary cell types, critically serving to maintain homeostasis in response to stress and diverse signals required for survival. In both anterior pituitary and endocrine hypothalamus, which originate from distinct ectodermal primordia, specific cell types can be readily distinguished on the basis of characteristic hormone or neuropeptide "signatures," recommending this system for probing the roles of specific families of transcription factors, and their regulation, in development. Our investigation of this system has provided the initial evidence for the determining roles of specific, novel transcription factors, insights into molecular mechanisms of synergistic activation and repression of gene expression, and the allosteric effects of the DNA site on transcriptional events. We have explored the role of a specific class of transcription factor in development of cortex and the audiovisual system, and as well as myelinating glia.
A description of our findings in development of the hypothalamic, pituitary axis is provided as an example of our research approach. 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 emerge 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. A similar paradigm operates in hypothalamic development , with a POU domain factor Brn-2, required for differentiation of these cell types in the PVH and SO nuclei.
We have recently identified novel co-activators (P/CIP) and co-repressors (NCoR) for the nuclear receptors and for other classes of transcription factor, and initially 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.
Two novel families of neuronally-expressed POU domain transcription factors have been identified, and using recombination of ES cells to generate mice null for each locus, we have discovered unexpected roles for these factors in development of specific neuronal systems, including the visual, auditory, and sensory systems. We are currently applying genetic, biochemical, and molecular biological approaches to understand precisely the molecular mechanisms that underlie brain development.
Kamei, Y. and L. Xu, T. Heinzel, J. Torchia, R. Kurokawa, B. Gloss, S-C. Lin, R.A. Heyman, D.W. Rose, C.K. Glass, and M.G. Rosenfeld. (1996). A CBP integrator complex mediates transcriptional activati
Sornson, M.W., W. Wu, J.S. Dasen, S. Flynn, D.J. Norman, S.M. O'Connell, I. Gukovsky, C. Carrière, A.K. Ryan, A.P. Miller, L. Zuo, A.S. Gleiberman, B. Andersen, W.G. Beamer, and Rosenfeld, M.G. (1996)
Heinzel, T., R.M. Lavinsky, T-M. Mullen, M. Söderström, C.D. Laherty, Joseph Torchia, Wen-Ming Yang, Gyan Brard, Sally D. Ngo, James R. Davie, E. Seto, R.N. Eisenman, D.W. Rose, C.K. Glass, and M.G. R
Torchia, J., D.W. Rose, J. Inostroza, Y. Kamei, S. Westin, C.K. Glass, and M.G. Rosenfeld. (1997). The transcriptional coactivator, p/CIP, binds CBP and mediates nuclear-receptor function. Nature (Art)
Treier, M., A.S. Gleiberman, S.M. O'Connell, D.P. Szeto, J.A. McMahon, A.P. McMahon, and M.G. Rosenfeld. (1998). Multistep Signaling Requirements for Pituitary Organogenesis In Vivo. Genes & Dev. 12 (1)
Korzus E., J. Torchia, D.W. Rose, L. Xu, R. Kurokawa, E.M. McInerney, T.M. Mullen, C.K. Glass, and M.G. Rosenfeld. (1998). Transcription factor-specific requirements for coactivators and their acetylt