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BMP-15 Draft


Structure & Interactions


Functions

Functions of BMP 15 include

BMP15 and Folliculogenesis

Folliculogenesis is an important process for the development and maintenance of fertility. Primordial follicles are stored in the ovary and throughout life are activated to go through morphological changes to become preovulatory follicles ready for ovulation, when the oocyte is released into the fallopian tube of the female reproductive tract.

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 [1]. This promotes granulosa cell proliferation via mitosis. BMP-15  promotes the change of primordial to primary or secondary follicles which are surrounded by several granulosa cell layers but doesn’t promote transition into preovulatory follicles [2].

File:Anatomy of the ovaries.jpg
Image 1: The stages of folliculogenesis in the ovary. BMP-15 function is crucial to promote proliferation of primordial follicles at stages 1-2 and via the inhibition of FSH receptor expression prevents follicles differentiation into the later stages of development (3-7).


BMP-15 prevents differentiation into preovulatory follicle by inhibiting FSH action in granulosa. FSH (follicle stimulating hormone) is released by the anterior pituitary as part of the hypothalamic-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 dependent progesterone production and luteinization, subsequently granulosa cells do not differentiate [2] [3].

As BMP-15 acts directly on granulosa cells it has an important influence on granulosa function including steroidogenesis inhibition of luteinization and differentiation of cumulus, without which would lead to infertility and lack of folliculogenesis [4].

Differences Between Species


Clinical Relevance

Mutations within the gene for BMP-15 have been associated with reproductive complications in females, due to the X-linked nature of the protein. Due to its role in folliculogenesis, mutations can lead to sub-fertility through decreased or absent folliculogenesis. In combination with GDF-9, mutant BMP-15 is also associated with ovulation defects, premature ovarian failure and other reproductive pathologies[5].

BMP-15 defects have been implicated in female sterility, PCOS, primary ovarian insufficiency (POI) and endometriosis. Women with PCOS have been noted to have higher levels of BMP-15[6], while missense mutations of the protein have been identified in females with POI[2].

Research has also found inherited mutant BMP-15 to be involved with the pathogenesis of hypergonadotropic ovarian failure[7]. 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 ovarian dysgenesis which results in hypergonadotropic ovarian failure[7].

The importance of BMP-15 in ovulation and folliculogenesis has been highlighted by research into Turner 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[2].

BMP-15 also has applications for animal reproduction, such as in mice and sheep. Reduced levels of BMP-15 in sheep have shown to increase ovulation, leading to larger litter sizes[8]. 


References

  1. ^ McNatty, K P; Moore, L G; Hudson, N L; Quirke, L D; Lawrence, S B; Reader, K; Hanrahan, J P; Smith, P; Groome, N P; Laitinen, M; Ritvos, O (2004-10). "The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology". Reproduction. 128 (4): 379–386. doi:10.1530/rep.1.00280. ISSN 1470-1626. {{cite journal}}: Check date values in: |date= (help)
  2. ^ a b c d Moore, R. Kelly; Shimasaki, Shunichi (2005-04-29). "Molecular biology and physiological role of the oocyte factor, BMP-15". Molecular and Cellular Endocrinology. 234 (1): 67–73. doi:10.1016/j.mce.2004.10.012. ISSN 0303-7207. Cite error: The named reference ":0" was defined multiple times with different content (see the help page).
  3. ^ Sanfins, Alexandra; Rodrigues, Patrícia; Albertini, David F. (2018-10). "GDF-9 and BMP-15 direct the follicle symphony". Journal of Assisted Reproduction and Genetics. 35 (10): 1741–1750. doi:10.1007/s10815-018-1268-4. ISSN 1058-0468. PMC 6150895. PMID 30039232. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  4. ^ Castro, Fernanda Cavallari de; Cruz, Maria Helena Coelho; Leal, Claudia Lima Verde (2015-12-26). "Role of Growth Differentiation Factor 9 and Bone Morphogenetic Protein 15 in Ovarian Function and Their Importance in Mammalian Female Fertility — A Review". Asian-Australasian Journal of Animal Sciences. 29 (8): 1065–1074. doi:10.5713/ajas.15.0797. ISSN 1011-2367. PMC 4932559. PMID 26954112.{{cite journal}}: CS1 maint: PMC format (link)
  5. ^ Castro, Fernanda Cavallari de; Cruz, Maria Helena Coelho; Leal, Claudia Lima Verde (2015-12-26). "Role of Growth Differentiation Factor 9 and Bone Morphogenetic Protein 15 in Ovarian Function and Their Importance in Mammalian Female Fertility — A Review". Asian-Australasian Journal of Animal Sciences. 29 (8): 1065–1074. doi:10.5713/ajas.15.0797. ISSN 1011-2367. PMC 4932559. PMID 26954112.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ Sanfins, Alexandra; Rodrigues, Patrícia; Albertini, David F. (2018-07-23). "GDF-9 and BMP-15 direct the follicle symphony". Journal of Assisted Reproduction and Genetics. 35 (10): 1741–1750. doi:10.1007/s10815-018-1268-4. ISSN 1058-0468.
  7. ^ a b Pasquale, Elisa Di; Beck-Peccoz, Paolo; Persani, Luca (2004-07-01). "Hypergonadotropic Ovarian Failure Associated with an Inherited Mutation of Human Bone Morphogenetic Protein-15 (BMP15) Gene". The American Journal of Human Genetics. 75 (1): 106–111. doi:10.1086/422103. ISSN 0002-9297. PMC 1181993. PMID 15136966.{{cite journal}}: CS1 maint: PMC format (link)
  8. ^ McNatty, K P; Moore, L G; Hudson, N L; Quirke, L D; Lawrence, S B; Reader, K; Hanrahan, J P; Smith, P; Groome, N P; Laitinen, M; Ritvos, O (2004-10). "The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology". Reproduction. 128 (4): 379–386. doi:10.1530/rep.1.00280. ISSN 1470-1626. {{cite journal}}: Check date values in: |date= (help)
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