Effect of Intracellular Interactions on the Processing and Secretion of Bone Morphogenetic Protein-15 (BMP-15) and Growth and Differentiation Factor-9

Wu, Liao; Moore, R. Kelly; Otsuka, Fumio; Shimasaki, Shunichi

doi:10.1074/jbc.m210598200

Cited by 144 publications

(146 citation statements)

References 29 publications

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“…missing the highly conserved cysteine residue that is involved in dimer formation (Elvin et al 2000, Chang et al 2002, McNatty et al 2003. Both GDF9 and BMP15 have been shown to produce homodimers and heterodimers when produced in the same cell in culture (Liao et al 2002). Clearly, these proteins do not need to be produced by the same cell to elicit their co-operative effects as combining conditioned media containing GDF9 and BMP15 just prior to adding to the granulosa cells is sufficient to observe the effect.…”

Section: Discussionmentioning

confidence: 95%

Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function

McNatty

Juengel²,

Reader³

et al. 2005

Reproduction

164

146

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The oocyte-secreted polypeptide growth factors, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15, also known as GDF9B) have both been shown to be essential for ovarian follicular growth and function. The effects of murine (m) and ovine (o) GDF9 as well as oBMP15, alone or together, on 3 H-thymidine uptake and progesterone and inhibin production by granulosa cells from rats were determined. Murine GDF9 stimulated thymidine incorporation by granulosa cells whereas oGDF9 and oBMP15 alone had no effect. However, oBMP15 given together with mGDF9 or oGDF9 was very potent in stimulating 3 H-thymidine incorporation by granulosa cells with a greater than 3-fold stimulation compared with any growth factor alone. The synergistic effect of oBMP15 and oGDF9 was almost completely blocked by antibodies generated against these growth factors when administered either alone or in combination. While neither GDF9 (murine or ovine) nor oBMP15 were able to modulate FSH-stimulated progesterone production on their own, FSH-stimulated progesterone production by granulosa cells was potently inhibited when BMP15 and GDF9 were administered together. Immunoreactive ainhibin levels increased more than 15-fold from granulosa cells when BMP15 and GDF9 were given together whereas consistent stimulatory effects of either growth factor alone were not observed. The effects of GDF9 and BMP15, when added together, were different than those observed for the growth factors alone. Therefore, we hypothesize that within the ovary, these oocyte-secreted growth factors co-operate to regulate proliferation and gonadotropin-induced differentiation of granulosa cells in mammals.Reproduction (

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Section: Discussionmentioning

confidence: 95%

Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function

McNatty

Juengel²,

Reader³

et al. 2005

Reproduction

164

146

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“…GDF9 is reported to form noncovalent homodimers, and also heterodimers, with BMP15, although the physiological relevance of the heterodimers remains to be established (Liao et al 2003). Furthermore, although ovine GDF9 and BMP15 are produced as nearly fully processed dimers in 293H cells, in ovine follicular fluid they exist as uncleaved premature proteins (McNatty et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep

Nicol

Bishop²,

Pong‐Wong³

et al. 2009

Reproduction

137

116

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The control of fecundity is critical in determining mammalian offspring survival. It is regulated principally by the ovulation rate, so that primates and large farm species commonly have a single offspring. Previously, several mutations have been identified in sheep which increase the naturally low ovulation rate; although in some cases homozygous ewes are infertile. In the present study we present a detailed characterization of a novel mutation in growth differentiation factor 9 (GDF9), found in Icelandic Thoka sheep. This mutation is a single base change (A1279C) resulting in a nonconservative amino acid change (S109R) in the C-terminus of the mature GDF9 protein, which is normally expressed in oocytes at all stages of development. Genotyping all animals for which reproductive records were available confirmed this mutation to be associated with increased fecundity in heterozygous ewes and infertility in homozygotes. Analysis of homozygote ovarian morphology and a number of genes normally activated in growing follicles showed that GDF9 was not involved in oocyte activation, but in subsequent development of the follicle. This study highlights the importance of oocyte factors in regulating fertility and provides new information for structural analysis and investigation of the potentially important sites of dimerization or translational modifications required to produce biologically active GDF9. It also provides the basis for the utilization of these animals to enhance sheep production.

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“…To obtain a construct of the sheep NOS3 promoter with mutations in the proximal AP-1 cisregulatory element (-TGAGTCA-, −685 to −679), site-directed mutagenesis was carried out by PCR using the 1305pNOS3/pGL3 plasmid as a template as described previously (Liao et al, 2003). Briefly, a primer set derived from the sequence of pGL3-Basic vector and the primer AP-1 sense (5′-CAACTAGATCTACAGGGGGTGGCG-3′; mutations positioned at −685, and −682 to −680 are underlined, these mutations created a BglII site) were used to generate the downstream PCR fragment.…”

Section: Site-directed Mutagenesis Of Ap-1 Site In Sheep Nos3 Promotermentioning

confidence: 99%

Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1

Qian¹,

Mata‐Greenwood²,

Wu³

et al. 2007

Molecular and Cellular Endocrinology

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Despite extensive studies have shown that increased endothelial nitric oxide synthase (NOS3) expression in the uterine artery endothelial cells (UAEC) plays a key role in uterine vasodilatation, the molecular mechanism controlling NOS3 expression in UAEC is unknown. According to the sheep NOS3 promoter sequence isolated in our laboratory, we hypothesize that the activator protein-1 (AP-1) site in the proximal sheep NOS3 promoter (TGAGTCA, -682 to -676) is important for NOS3 expression. We developed a c-Jun adenoviral expression system to overexpress c-Jun protein into UAEC to investigate the effects of c-Jun/AP-1 on NOS3 expression. Basal levels of c-Jun protein and mRNA were detected in UAEC. C-Jun protein was overexpressed in a concentration and timedependent fashion in UAEC infected with sense c-Jun (S-c-Jun), but not sham and antisense c-Jun (A-c-Jun) adenoviruses. Infection with S-c-Jun adenovirus (25 MOI, multiplicity of infection) resulted in efficient c-Jun protein overexpression in UAEC up to 3 days. In S-c-Jun, but not sham and A-c-Jun adenovirus infected UAEC, NOS3 mRNA and protein levels were increased (P<0.05) compared to noninfected controls. Increased NOS3 expression was associated with increased total NOS activity. Transient transfections showed that c-Jun overexpression augmented the transactivation of the sheep NOS3 promoter-driven luciferase/reporter constructs with the AP-1 site but not of deletion constructs without the AP-1 site. When the AP-1 site was mutated, c-Jun failed to trans-activate the sheep NOS3 promoter. AP-1 DNA binding activity also increased in c-Jun overexpressed UAEC. Lastly, the pharmacological AP-1 activator phorbol myristate acetate increased AP-1 binding, trans-activated the wild-type but not the AP-1 mutant NOS3 promoter and dose-dependently stimulated UAEC NOS3 and c-Jun protein expression. Hence, our data show that c-Jun/AP-1 regulates NOS3 transcription involving the proximal AP-1 site in the 5′-regulatory region of the sheep NOS3 gene. Keywordsc-Jun/AP-1; endothelial nitric oxide synthase expression; uterine artery endothelial cells

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Effect of Intracellular Interactions on the Processing and Secretion of Bone Morphogenetic Protein-15 (BMP-15) and Growth and Differentiation Factor-9

Cited by 144 publications

References 29 publications

Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function

Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function

Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep

Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1

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