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Species Differences in the Expression and Activity of Bone Morphogenetic Protein 15.
MedLine Citation:
PMID:  23284103     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Oocyte-derived bone morphogenetic protein 15 (BMP15) regulates ovulation rate and female fertility in a species-specific manner, being important in humans and sheep and largely superfluous in mice. To understand these species differences, we have compared the expression and activity of human, murine, and ovine BMP15. In HEK293F cells, human BMP15 is highly expressed (120 ng/ml), ovine BMP15 is poorly expressed (15 ng/ml), and murine BMP15 is undetectable. Because BMP15 synthesis is dependent upon interactions between the N-terminal prodomain and the C-terminal mature domain, we used site-directed mutagenesis to identify four prodomain residues (Glu(46), Glu(47), Leu(49), and Glu(50)) that mediate the high expression of human BMP15. Substituting these residues into the prodomains of murine and ovine BMP15 led to significant increases in growth factor expression; however, maximal expression was achieved only when the entire human prodomain was linked to the mature domains of the other species. Using these chimeric constructs, we produced and purified murine and ovine BMP15 and showed that in a COV434 granulosa cell bioassay, these molecules displayed little activity relative to human BMP15 (EC(50) 0.2nM). Sequence analysis suggested that the disparity in activity could be due to species differences at the type I receptor binding interface. Indeed, murine BMP15 activity was restored when specific residues through this region (Pro(329)/Tyr(330)) were replaced with the corresponding residues (Arg(329)/Asp(330)) from human BMP15. The identified differences in the expression and activity of BMP15 likely underlie the relative importance of this growth factor between species.
Authors:
Sara L Al-Musawi; Kelly L Walton; Derek Heath; Courtney M Simpson; Craig A Harrison
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-2
Journal Detail:
Title:  Endocrinology     Volume:  -     ISSN:  1945-7170     ISO Abbreviation:  Endocrinology     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Prince Henry's Institute of Medical Research (S.L.A.-M., K.L.W., C.M.S., C.A.H.), Clayton, Victoria 3168, Australia; School of Biological Sciences (D.H.), Victoria University of Wellington, Wellington 6140, New Zealand; and Department of Biochemistry and Molecular Biology (C.M.S., C.A.H.), Monash University, Clayton Victoria 3800, Australia.
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