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FRISC: The Faculty Research Interests Science Comparator |
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Professor of Pharmacology
Investigator, Howard Hughes Medical Institute
Cell Regulation
Integrative Biology
Office: (214) 648-5090
FAX: (214) 648-5087
Email: dgarbe@mednet.swmed.edu
Research in this laboratory focuses on sperm
development, the molecular basis of fertilization, and a family of cell surface receptors
known as guanylyl cyclases. By virtue of initial work in the sea urchin, egg peptides were
discovered that acted in a species-specific manner to stimulate motility and cause
chemotaxis. The receptors for these peptides were shown to be guanylyl cyclases, which
signal through the second messenger, cyclic GMP. Subsequently, the family was discovered
in mammals, as well as a host of other animals, where members of the family regulate a
diversity of physiological events such as blood pressure, vision and intestinal secretion.
Four putative guanylyl cyclase receptors in the
mammal remain orphans and one of the goals of the laboratory is to identify the presumed
ligands. Of the four, two are expressed in the retina, one in a small subset of olfactory
neurons and one in a number of peripheral tissues such as skeletal muscle, lung and
intestine. Studies on sperm development concentrate on technologies to promote the
formation of haploid spermatids from spermatogonia. Such work requires micromanipulation
of the gametes and nuclear transfer expertise.
Studies on the molecular basis of fertilization
have now moved to the mammal. One sperm-specific protein isolated binds to the
extracellular matrix of the egg in a species-specific manner and is homologous to von
Willebrand factor. Recently, the focus has been on the development of signal peptide trap
technology to define the membrane proteins and secreted proteins of the egg and sperm cell
as well as of other cells potentially involved in gamete signaling. The library of
candidate proteins will provide a source of potential key players in the fertilization
process.
Selected Publications:
Chrisman, T.D. and Garbers, D.L. (1999).
Reciprocal antagonism coordinates C-type natriuretic peptide and mitogen-signaling
pathways in firbroblasts. J.Biol.Chem . 274, 4293-4299.
Foster, D.C. and Garbers, D.L. (1998). Dual role
for adenine nucleotides in the regulation of the atrial natriuretic peptide receptor,
guanylyl cyclase-A. J.Biol.Chem. 273, 16311-16318.
Gao, Z. and Garbers, D.L. (1998). Species
diversity in the structure of zonadhesin, a sperm-specific membrane protein containing
multiple cell adhesion molecule-like domains. J.Biol.Chem. 272, 23064-23068.
Kelsell, R.E., Gregory-Evans, K., Payne, A.M.,
Perrault, I., Kaplan, J., Yang, R.B., Garbers, D.L., Bird, A.C., Moore, A.T., and Hunt,
D.M. (1998). Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant
cone-rod dystrophy. Hum.Mol.Genet . 7, 1179-1184.
Schulz, S., Wedel, B.J., Matthews, A., and
Garbers, D.L. (1998). The cloning and expression of a new guanylyl cyclase orphan
receptor. J.Biol.Chem. 273, 1032-1037.
Sunahara, R.K., Beuve, A., Tesmer, J.J.G.,
Sprang, S.R., Garbers, D.L., and Gilman, A.G. (1998). Exchange of substrate and inhibitor
specificities between adenylyl and guanylyl cyclases. J.Biol.Chem. 273,
16332-16338.
Baude, E.J., Arora, V.K., Yu, S., Garbers, D.L.,
and Wedel, B.J. (1997). The cloning of a Caenorhabditis elegans guanylyl cyclase and the
construction of a ligand-sensitive mammalian/nematode chimeric receptor. J.Biol.Chem.
272, 16035-16039.
Julifs, D.M., Fülle, H.-J., Zhao, A.Z., Houslay,
M.D., Garbers, D.L., and Beavo, J.A. (1997). A subset of olfactory neurons that
selectively express cGMP-stimulated phosphodiesterase (PDE2) and guanylyl cyclcase-D
define a unique olfactory signal transduction pathway. Proc.Natl.Acad.Sci.U.S.A .
94, 3388-3395.
Schulz, S., Lopez, M.J., Kuhn, M., and Garbers,
D.L. (1997). Disruption of the guanylyl cyclase-C gene leads to a paradoxical phenotype of
viable but heat-stable enterotoxin-resistant mice. J.Clin.Invest. 100, 1590-1595.
Yu, S., Avery, L., Baude, E., and Garbers, D.L.
(1997). Guanylyl cyclase expression in specific sensory neurons: A new family of
chemosensory receptors. Proc.Natl.Acad.Sci.U.S.A. 94, 3384-3387.
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