ライフサイエンスコーパス: BMP-15

1 ions in the production of the mature form of BMP-15.

2 bout the signaling pathway and receptors for BMP-15.

3 cyte must play a role in the GC responses to BMP-15.

4 rotein is significantly lower than wild-type BMP-15.

5 ng the stimulation of Smad1/5/8 signaling by BMP-15.

6 the target cells and biological functions of BMP-15.

7 ormones as the first biological functions of BMP-15.

8 identifies GCs as the first target cells for BMP-15.

9 is is clearly distinct from the mechanism of BMP-15 action, which causes the suppression of basal FSH

10 ibitor of ERK1/2 phosphorylation, suppresses BMP-15 activity on GC mitotsis but not on FSH-induced pr

11 Treatment with BMP-15 alone exerted no significant effect on the basal

12 By contrast, BMP-15 alone had no effect on steroidogenesis.

13 BMP-15 also stimulated promoter activity of a selective

14 Bone morphogenetic protein-15 (BMP-15), an oocyte growth factor belonging to the transf

15 e feedback system governed by oocyte-derived BMP-15 and GC-derived KL, and demonstrates that the mito

16 We demonstrate the first evidence that both BMP-15 and GDF-9 can form non-covalent homodimers when e

17 y, heterozygous ewes with a mutation in both BMP-15 and GDF-9 exhibit higher fertility than those hav

18 d that GCNF bound to DR0 elements within the BMP-15 and GDF-9 gene promoters and repressed their repo

19 Here, we have produced recombinant human BMP-15 and GDF-9 that carry the mutations identified in

20 essed with wild-type GDF-9, the secretion of BMP-15 and GDF-9 was significantly reduced, suggesting t

21 Here we show that, unlike BMP-15 and GDF-9, BMP-6 lacks mitogenic activity on rat

22 omatic cells by regulating the expression of BMP-15 and GDF-9, to affect female fertility.

23 fill this gap in our knowledge, recombinant BMP-15 and its antibody were produced and used to determ

24 demonstrates that the mitotic activities of BMP-15 and KL for GCs depend on this oocyte-GC communica

25 tified in those sheep, i.e. I31D and S99I in BMP-15 and S77F in GDF-9.

26 rived factor, bone morphogenetic protein-15 (BMP-15) and a GC-derived factor, kit ligand (KL), both o

27 Bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9 (GDF-9)

28 Bone morphogenetic protein-15 (BMP-15) and growth and differentiation factor-9 (GDF-9)

29 ng molecules, bone morphogenetic protein 15 (BMP-15) and growth differentiation factor 9 (GDF-9), wer

30 pansion, and this activity was attenuated by BMP-15 antibody.

31 Interestingly, when GDF-9 and BMP-15 are co-expressed the processing of both proprotei

32 ular domain was most effective in inhibiting BMP-15 bioactivity on FSH-induced progesterone productio

33 ivation of the MAPK pathway is necessary for BMP-15 biological activity and found that the addition o

34 However, unlike BMP-15, BMP-6 inhibited forskolin- but not 8-bromo-cAMP-

35 This BMP-6 activity resembles BMP-15 but differs from GDF-9 activities.

36 BMP-6 also exhibited similar action to BMP-15 by attenuating the steady state mRNA levels of FS

37 ocyte-derived bone morphogenetic protein-15 (BMP-15) can directly modulate follicle-stimulating hormo

38 34, we have now found that administration of BMP-15 causes a rapid and transient phosphorylation, thu

39 Based on the biological role of BMP-15, defects in the production of mouse BMP-15 mature

40 In striking contrast, BMP-15 did not change the forskolin-induced levels of th

41 we investigate underlying mechanisms of this BMP-15 effect.

42 Moreover, KL, like BMP-15, exhibited mitotic activity on GCs in the presenc

43 antibody were produced and used to determine BMP-15 expression and bioactivity.

44 es KL expression in GCs, whereas KL inhibits BMP-15 expression in oocytes, thus forming a negative fe

45 ies of cell lines, which express recombinant BMP-15, GDF-9, or both, and investigated whether they fo

46 ble-oocyte follicles, indicative of aberrant BMP-15/GDF-9 expression, were observed in GCNF(fl/fl)Zp3

47 dividually, while when both are co-expressed BMP-15/GDF-9 heterodimers are produced.

48 ations in the bone morphogenetic protein 15 (BMP-15) gene cause female infertility in the monoovulato

49 Although the role of BMP-15 in female reproduction has progressively deserved

50 receptor completely abolished the effect of BMP-15 in inducing cumulus expansion.

51 nces, we investigated the functional role of BMP-15 in the mouse ovary.

52 it neutralizing antibody markedly suppressed BMP-15-induced GC mitosis, suggesting that the oocyte mu

53 Further, we found that BMP-15 induces cumulus expansion in mouse cumulus-oocyte

54 Consistent with the mRNA data, BMP-15 inhibited the biological response of FSH, but not

55 d stable transformants expressing the mutant BMP-15 (InvBMP-15) alone or together with GDF-9.

56 t folliculogenesis, supporting the idea that BMP-15 is a physiological regulator of follicle cell pro

57 We found that BMP-15 is a potent stimulator of GC proliferation, and i

58 This result indicates that BMP-15 is a selective modulator of FSH action.

59 Based on these results, we propose that BMP-15 is an important determinant of FSH action through

60 we found that the functional mature form of BMP-15 is barely detectable in the mouse oocytes until j

61 Significantly, BMP-15 is the first growth factor that can coordinate GC

62 Bone morphogenetic protein 15 (BMP-15) is an oocyte-secreted factor that has raised par

63 rowth factor, bone morphogenetic protein-15 (BMP-15), is one such molecule.

64 However, BMP-15 markedly inhibited the FSH-induced increases in t

65 f BMP-15, defects in the production of mouse BMP-15 mature protein could correlate with the high ovul

66 that the defects in the production of mouse BMP-15 mature protein depend on the presence of the mous

67 there are defects in the production of mouse BMP-15 mature protein in an in vitro system of transfect

68 We found that, although human BMP-15 mature protein is readily produced, there are def

69 ificant reduction in the production of human BMP-15 mature protein.

70 BMP-15 mRNA and protein were shown to be co-expressed in

71 Since BMP-15 mutant sheep, called Inverdale, exhibit severe de

72 suggesting that the mechanisms by which the BMP-15 mutations affect sheep fertility occurs at the le

73 found that when individually expressed, both BMP-15 mutations had no effect on the processing, secret

74 ific differences in the phenotypes caused by BMP-15 mutations may thus be attributed to the temporal

75 contrast to the recent studies on GDF-9 and BMP-15, nothing is known about the biological function o

76 results are consistent with the phenotype of BMP-15-null mice, which exhibit normal folliculogenesis

77 ere compare the molecular characteristics of BMP-15 of polyovulatory mice with that of monoovulatory

78 Thus, the inhibitory effect of BMP-15 on FSH action must be upstream of cAMP signaling.

79 FSH function, we investigated the effect of BMP-15 on FSH bioactivity.

80 ) proliferation and differentiation; namely, BMP-15 promotes GC mitosis, suppresses follicle-stimulat

81 protein depend on the presence of the mouse BMP-15 proregion.

82 of different combinations of mouse and human BMP-15 proregions, cleavage sites, and mature regions in

83 We have previously demonstrated that BMP-15 regulates granulosa cell (GC) proliferation and d

84 the polyovulatory mouse, loss-of-function of BMP-15 results only in reduced ovulation rate.

85 Interestingly, BMP-15 severely reduced the levels of FSH receptor mRNA

86 Moreover, BMP-15 stimulated the expression of EGF-like growth fact

87 system of rat oocytes and GCs and found that BMP-15 stimulates KL expression in GCs, whereas KL inhib

88 In contrast, BMP-15 stimulation of Smad2 phosphorylation was very wea

89 ells co-expressing wildtype GDF-9 and mutant BMP-15, suggesting a possible mechanism for the extreme

90 here are species-specific differences in the BMP-15 system that may play causal roles in the differen

91 en mutant GDF-9 was co-expressed with mutant BMP-15, the secretion levels of both proteins were signi

92 However, when mutant BMP-15 was co-expressed with wild-type GDF-9, the secret

93 To identify the receptors for BMP-15, we utilized recombinant extracellular domains of

94 most effectively co-immunoprecipitates with BMP-15, whereas BMP receptor type II extracellular domai