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Gene
Expression and Cellular Signaling in Reproductive Developm ent
My laboratory seeks to understand the molecular and genetic pathways leading
to mammalian reproductive development. Disorders in sexual development
are prevalent among the human population and have contributed immensely
to the identification of some mammalian sex-determination genes. However,
the link between these genes and the molecular mechanisms of sex differentiation
has not been established. To begin defining the molecular events in sex
determination we have focused on how the MÙllerian inhibiting substance
(MIS) gene is regulated. We now know that the orphan nuclear receptor
SF-1 is the major regulator of MIS. SF-1 is also an essential regulator
of endocrine organogenesis, prompting us to ask some basic mechanistic
questions about how this unusual member of the nuclear receptor superfamily
participates in sex determination. In males, MIS promotes regression of
the MÙllerian duct (female reproductive tract) via a paracrine-mediated
programmed cell death mechanism.Thus, we also want to define the molecular
components of this dynamic morphogenetic event. Because MIS is vital for
proper sexual differentiation and function, our research may help to elucidate
the molecular basis of human sexual disorders, reproductive abnormalities,
and general mechanisms underlying mammalian development.
Selected Publications:
Nachtigal, M.W., Hirokawa, Y., VanHouten-Enyeart, D., Flanagan, J.N, Hammer,
G.D. and H.A. Ingraham, Wilm's Tumor and Dax-1 modulate the orphan nuclear
receptor, SF-1 in sex-specific gene expression. Cell 93:445-454 (1998).
Roberts, L.M., Hirokawa, Y., Nachtigal, M.W. and H.A. Ingraham. Paracrine
mediated apoptosis in mammalian reproductive tract morphogenesis. Developmental
Biology 208:110-122 (1999).
Hammer, G.D., Krylova, I., Simpson, K., Zhang, Y., Darimont, B.D. Krylova,
I., Weigel, N.L. and H.A. Ingraham. Phosphorylation State of SF-1 modulates
nuclear receptor cofactor recruitment: integration of hormone signaling
and SF-1 in Reproduction and the Stress Response. Molecular Cell 3: 521-526
(1999).
Contact Information:
Email: hollyi@itsa.ucsf.edu
Phone: 415/ 476-2731
Address: Box 1230, 1550 4th Street, Room 248 E
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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