Bone morphogenetic protein 15 (BMP-15) is aprotein that in humans is encoded by the BMP15gene. It is involved infolliculogenesis, the process in which primordial follicles develop intopre-ovulatory follicles.
The BMP-15gene is located on theX-chromosome and using Northern blot analysis BMP-15mRNA is locally expressed within theovaries inoocytes only after they have started to undergo the primary stages of development.[5][6] BMP-15 is translated as apreproprotein that is composed of a singlepeptide, which contains a proregion and a smaller mature region.[6]Intracellular processing then leads to the removal of the proregion, leaving the biologically active mature region to perform the functions.[5] This protein is a member of theTransforming growth factor beta (TGF-β) superfamily and is a paracrine signalling molecule.[7] Most active BMPs have a common structure, in which they contain 7cysteines, 6 of which form three intramoleculardisulphide bonds and the seventh being involved in the formation of dimers with other monomers.[7] BMP-15 is an exception to this as the molecule does not contain the seventh cysteine.[7] Instead in BMP-15 the fourth cysteine is replaced by aserine.[7]
BMP-15 andGDF9 interact with each other and work synergistically to have similar interactions with the target cell.[8] BMP15 can act as aheterodimer with GDF9 or on its own as ahomodimer.[8] In most of the BMP family heterodimers and homodimers form as the seventh cysteine is involved in the formation of acovalent bond, leading thedimerization.[9] However, in the BMP-15 the homodimers form as a non-covalent bond is present between two BMP-15 subunits.[7]
Functions of BMP-15 include[10]
Folliculogenesis is an important process for the development and maintenance offertility.Primordial follicles are stored in the ovary and throughout life are activated to go through morphological changes to becomepreovulatory follicles ready forovulation, when theoocyte is released into thefallopian tube of the female reproductive tract.[11]
BMP-15 main functions are crucial for the beginning of folliculogenesis as seen in Image 1. The primordial follicle is made up of the oocyte and a single layer of flattened granulosa cells. BMP-15 is released from the oocyte into the surrounding granulosa tissue where it binds to two membrane bound receptors on granulosa cells.[9] This promotes granulosa cell proliferation viamitosis. BMP-15 promotes the change of primordial to primary and secondary follicles which are surrounded by several granulosa cell layers but doesn't promote transition into preovulatory follicles.[12] BMP-15 prevents differentiation into preovulatory follicle by inhibiting FSH action in granulosa. FSH is released by theanterior pituitary as part of thehypothalamic-pituitary-gonadal axis and promotes the differentiation of early follicles into later preovulatory ones. BMP-15 prevents this transition by inhibiting the production of FSH receptor mRNA in granulosa cells. Therefore, FSH cannot bind to the granulosa cells, this inhibits FSH dependentprogesterone production andluteinization, subsequently granulosa cells do not differentiate.[12][8]
As BMP-15 acts directly on granulosa cells it has an important influence on granulosa function includingsteroidogenesis inhibition of luteinization and differentiation of cumulus, without which would lead to infertility and lack of folliculogenesis.[13]
The use of mammalian species other than human is often used in research to learn more about human biology.
Two breeds of sheep,Inverdale and Hanna, are naturallyheterozygous carriers ofpoint mutations in the BMP-15 gene.[9] These point mutations result in higherovulation rates and larger litter sizes than sheep strains with awildtype BMP-15genotype.[9] Thissuper-fertility was mimicked later throughimmunization of wildtypeewes against BMP-15 using various immunisation techniques.[9] Sheep carryinghomozygousalleles for the Inverdale and Hanna BMP-15 mutations areinfertile, as they havestreak ovaries and the primary stage offolliculogenesis is inhibited.[9] These studies suggest that BMP-15 plays a vital role in the normal regulation of folliculogenesis and ovulation in sheep.[12]
In mice, the BMP-15homologue is not as physiologically important.[9] Upontargeted deletion of abmp15exon, the mice presented with onlysubfertility inhomozygotes and no clear aberrant phenotype inheterozygotes.[9] The homozygous mutant mice did not suffer from reduced folliculogenesis or impactedfollicle progression, unlike in the sheep homologueknockout experiments.[9] The subfertility seen in the homozygous mutant phenotype was attributed to defective ovulation and reduced viability of embryos. Here it can be stated that BMP-15 is not as vital for normal female mouse fertility as it is for sheep.[9]
Humans display a similarphenotype to the Inverdale/Hanna sheep in regards to female fertility.[9] In women, a mutation in BMP-15 is linked tohypergonadotropic ovarian failure due toovarian dysgenesis.[9] In this case, the researchers were able to identify that the father of the two sisters displaying this mutation had no documented phenotype associated with the mutation, so BMP-15 appears to only affect females.[9] In slight contrast to the reports on sheep, the women in this study were heterozygous for the BMP-15 mutation but exhibited streak ovaries, a phenotype very similar to the one seen in homozygousmutant ewes.[9] The sisters presented withprimary amenorrhea, showing that BMP-15 is also vital to normal human female fertility, concordant with the sheep model.[9]
The main theory for this stark difference between mammalian species relates to the number of follicles normally ovulated in each cycle by each species.[9] Humans and sheep aremono-ovulatory, potentially explaining the difference in litter size observed in mutant individuals.[9] As mice arepoly-ovulatory, the role of BMP-15 in female mouse fertility may not be as obvious.[9]
Mutations within thegene for BMP-15 have been associated with reproductive complications in females, due to theX-linked nature of the protein. Due to its role infolliculogenesis, mutations can lead to sub-fertility through decreased or absent folliculogenesis. In combination withGDF-9, mutant BMP-15 is also associated withovulation defects,premature ovarian failure and other reproductive pathologies.[13]
BMP-15 defects have been implicated in femalesterility,Polycystic Ovary Syndrome (PCOS), primary ovarian insufficiency (POI) andendometriosis. Women with PCOS have been noted to have higher levels of BMP-15,[8] while missense mutations of the protein have been identified in females with POI.[9]
Research has also found inherited mutant BMP-15 to be involved with the pathogenesis ofhypergonadotropic ovarian failure.[8] This condition develops due to BMP-15 role in folliculogenesis, and the errors that occur when a mutant gene is inherited. The protein is linked to familial ovariandysgenesis which results in hypergonadotropic ovarian failure.[8]
The importance of BMP-15 in ovulation and folliculogenesis has been highlighted by research intoTurner syndrome, a chromosomal abnormality where females are missing a complete or partial X chromosome. Depending on the chromosomal mutation, BMP-15 gene dosage varies and impacts ovarian development in Turner syndrome patients. The gene is thus involved in determining the extent of the ovarian defects present in Turner syndrome.[9]
BMP-15 is also present in animals and involved in reproduction, such as in mice and sheep. Reduced levels of BMP-15 in sheep have shown to increase ovulation, leading to larger litter sizes.[9]
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
