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J. Biol. Chem., Vol. 276, Issue 35, 32889-32895, August 31, 2001
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From the Department of Reproductive Medicine, University of
California San Diego, School of Medicine,
La Jolla, California 92093-0633
The process of ovarian
folliculogenesis is composed of proliferation and differentiation of
the constitutive cells in developing follicles. Growth factors emitted
by oocytes integrate and promote this process. Growth differentiation
factor-9 (GDF-9), bone morphogenetic protein (BMP)-15, and BMP-6 are
oocyte-derived members of the transforming growth factor-
Biological Function and Cellular Mechanism of Bone Morphogenetic
Protein-6 in the Ovary*
,
superfamily. In contrast to the recent studies on GDF-9 and BMP-15,
nothing is known about the biological function of BMP-6 in the ovary.
Here we show that, unlike BMP-15 and GDF-9, BMP-6 lacks mitogenic
activity on rat granulosa cells (GCs) and produces a marked decrease in
follicle-stimulating hormone (FSH)-induced progesterone
(P4) but not estradiol (E2) production,
demonstrating not only the first identification of GCs as BMP-6 targets
in the ovary but also its selective modulation of FSH action in
steroidogenesis. This BMP-6 activity resembles BMP-15 but differs from
GDF-9 activities. BMP-6 also exhibited similar action to BMP-15 by
attenuating the steady state mRNA levels of FSH-induced
steroidogenic acute regulatory protein (StAR) and P450 side-chain
cleavage enzyme (P450scc), without affecting P450 aromatase mRNA
level, supporting its differential function on FSH-regulated
P4 and E2 production. However, unlike BMP-15,
BMP-6 inhibited forskolin- but not 8-bromo-cAMP-induced P4
production and StAR and P450scc mRNA expression. BMP-6 also
decreased FSH- and forskolin-stimulated cAMP production, suggesting
that the underlying mechanism by which BMP-6 inhibits FSH action most likely involves the down-regulation of adenylate cyclase activity. This
is clearly distinct from the mechanism of BMP-15 action, which causes
the suppression of basal FSH receptor (FSH-R) expression, without
affecting adenylate cyclase activity. As assumed, BMP-6 did not alter
basal FSH-R mRNA levels, whereas it inhibited FSH- and forskolin-
but not 8-bromo-cAMP-induced FSH-R mRNA accumulation. These studies
provide the first insight into the biological function of BMP-6 in the
ovary and demonstrate its unique mechanism of regulating FSH action.
*
This work was supported in part by the University of
California San Diego Academic Senate Grant RY 440M and NICHD Grant
U54HD12303 from the National Institutes of Health as part of
Specialized Cooperative Centers Program in Reproduction Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a fellowship grant from the Lalor Foundation.
§
Supported by National Institutes of Health Training Grant T32
HD07203-17.
¶
To whom correspondence should be addressed: Dept. of
Reproductive Medicine, University of California, School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0633. Tel.: 858-822-1414; Fax:
858-822-1482; E-mail address: sshimasaki@ucsd.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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