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J. Biol. Chem., Vol. 278, Issue 6, 3713-3719, February 7, 2003
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From the Department of Reproductive Medicine, University of
California San Diego, School of Medicine, La Jolla, California
92093-0633
Bone morphogenetic protein-15
(BMP-15) and growth and differentiation factor-9 (GDF-9) are members of
the transforming growth factor-
Effect of Intracellular Interactions on the Processing and
Secretion of Bone Morphogenetic Protein-15 (BMP-15) and Growth and
Differentiation Factor-9
IMPLICATION OF THE ABERRANT OVARIAN PHENOTYPE OF BMP-15 MUTANT
SHEEP*
,
superfamily. Both molecules are
closely related in their primary structures and share a nearly
identical spatiotemporal expression pattern in the oocyte during
folliculogenesis in mammals. Here we have established a series of cell
lines, which express recombinant BMP-15, GDF-9, or both, and
investigated whether they form homodimers and/or heterodimers. We
demonstrate the first evidence that both BMP-15 and GDF-9 can form
non-covalent homodimers when expressed individually, while when both
are co-expressed BMP-15/GDF-9 heterodimers are produced. Interestingly,
when GDF-9 and BMP-15 are co-expressed the processing of both
proproteins are significantly impaired as compared with that of the
singly expressed proproteins, suggesting that the proprotein
heterodimer is less susceptible to proteolytic cleavage than the
individual homodimers. Since BMP-15 mutant sheep, called Inverdale,
exhibit severe defects in ovarian function we have also established
stable transformants expressing the mutant BMP-15 (InvBMP-15) alone or together with GDF-9. Although InvBMP-15 was previously predicted to be
unable to form homodimers, we show here that it does form non-covalent
dimers; however, the processing efficiency of InvBMP-15 proprotein is
significantly lower than wild-type BMP-15. Surprisingly, when GDF-9 is
co-expressed, the processing and secretion of InvBMP-15 is abolished,
and the processing of GDF-9 is also severely impaired, suggesting that
the heterodimers of InvBMP-15/GDF-9 proproteins are not
susceptible to proteolytic cleavage and thus degrade in the cells.
Based on these findings we propose a novel hypothesis that a decrease
in GDF-9 secretion may be involved in causing infertility in homozygous
Inverdale ewes.
*
This work was supported in part by National Institutes of
Health Grant RO1 HD41494 and the NICHD, National Institutes of Health through cooperative agreement (U54HD12303) 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 National Institutes of Health Fellowship Grant F32 HD41320.
§
Supported by a fellowship grant from the Lalor Foundation.
¶
To whom correspondence should be addressed: Dept. of
Reproductive Medicine, University of California at San Diego, School of
Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0633. E-mail address:
sshimasaki@ucsd.edu.
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