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J. Biol. Chem., Vol. 275, Issue 50, 39523-39528, December 15, 2000
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From the Department of Reproductive Medicine, University of
California, San Diego, School of Medicine,
La Jolla, California 92093-0633
In developing ovarian follicles, the regulation
of cell proliferation and differentiation is tightly coordinated.
Precisely how this coordination is achieved is unknown, but recent
observations have suggested that molecules emitted by the oocyte are
involved in the process. The newly discovered oocyte-specific growth
factor, bone morphogenetic protein-15 (BMP-15), is one such molecule. At present, nothing is known about the target cells and biological functions of BMP-15. To fill this gap in our knowledge, recombinant BMP-15 and its antibody were produced and used to determine BMP-15 expression and bioactivity. BMP-15 mRNA and protein were shown to
be co-expressed in oocytes throughout folliculogenesis, supporting the
idea that BMP-15 is a physiological regulator of follicle cell
proliferation and/or differentiation. To test this, we used primary
cultures of rat granulosa cells (GCs). We found that BMP-15 is a potent
stimulator of GC proliferation, and importantly, the mitogenic effect
was follicle-stimulating hormone (FSH)-independent. By contrast, BMP-15
alone had no effect on steroidogenesis. However, it produced a marked
decrease in FSH-induced progesterone production, but had no effect on
FSH-stimulated estradiol production. This result indicates that BMP-15
is a selective modulator of FSH action. In summary, this study
identifies GCs as the first target cells for BMP-15. Moreover, it
identifies the stimulation of GC proliferation and the differential
regulation of two crucial steroid hormones as the first biological
functions of BMP-15. Significantly, BMP-15 is the first growth factor
that can coordinate GC proliferation and differentiation in a way that
reflects normal physiology.
Bone Morphogenetic Protein-15
IDENTIFICATION OF TARGET CELLS AND BIOLOGICAL FUNCTIONS*
*
This work was supported in part by the Lalor Foundation; by
University of California, San Diego Academic Senate Grant RY 440M; and
by NICHD, National Institutes of Health through cooperative agreement
(Grant U54HD12303) as part of the 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.
To whom correspondence should be addressed: Dept. of
Reproductive Medicine, University of California, San Diego, School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0633. E-mail:
sshimasaki@ucsd.edu.
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