Growth differentiation factor-9 is required during early ovarian folliculogenesis

GROWTH factors synthesized by ovarian somatic cells directly affect oocyte growth and function1–6, but it is unclear whether oocyte-secreted factors6–9 play a reciprocal role in modulating somatic cell functions in vivo. During the functional analysis of members of the transforming growth factor-β superfamily in mouse development10–15, we have uncovered a new family member, growth differentiation factor-9 (GDF-9), which is required for ovarian folliculogenesis. GDF-9 messenger RNA is synthesized only in the oocyte from the primary one-layer follicle stage until after ovulation16,17. Here we analyse ovaries from GDF-9-deficient female mice and demonstrate that primordial and primary one-layer follicles can be formed, but there is a block in follicular development beyond the primary one-layer follicle stage which leads to complete infertility. Oocyte growth and zona pellucida formation proceed normally, but other aspects of oocyte differentiation are compromised. Thus, GDF-9 is the first oocyte-derived growth factor required for somatic cell function in vivo.

[1]  A. Bradley,et al.  α-lnhibin is a tumour-suppressor gene with gonadal specificity in mice , 1992, Nature.

[2]  S. McGrath,et al.  Oocyte-specific expression of growth/differentiation factor-9. , 1995, Molecular endocrinology.

[3]  J. Eppig.  Oocyte-somatic cell communication in the ovarian follicles of mammals , 1994 .

[4]  D. Albertini.  Cytoplasmic microtubular dynamics and chromatin organization during mammalian oogenesis and oocyte maturation. , 1992, Mutation research.

[5]  D. Albertini,et al.  Meiotic competence acquisition is associated with the appearance of M-phase characteristics in growing mouse oocytes. , 1991, Developmental biology.

[6]  D. Keisler,et al.  Characterization of ovarian follicular cysts and associated endocrine profiles in dairy cows. , 1995, Biology of reproduction.

[7]  D. Albertini,et al.  Oogenesis: Chromatin and microtubule dynamics during meiotic prophase , 1990, Molecular reproduction and development.

[8]  T. Pedersen,et al.  Proposal for a classification of oocytes and follicles in the mouse ovary. , 1968, Journal of reproduction and fertility.

[9]  K. Zsebo,et al.  Effects of the steel gene product on mouse primordial germ cells in culture , 1991, Nature.

[10]  C. Brannan,et al.  Requirement for mast cell growth factor for primordial germ cell survival in culture , 1991, Nature.

[11]  S. Nishikawa,et al.  Effect of Steel factor and leukaemia inhibitory factor on murine primordial germ cells in culture , 1991, Nature.

[12]  S. J. Lee,et al.  GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. , 1993, The Journal of biological chemistry.

[13]  B. Vanderhyden,et al.  Mouse oocytes promote proliferation of granulosa cells from preantral and antral follicles in vitro. , 1992, Biology of reproduction.

[14]  K. Manova,et al.  Gonadal expression of c-kit encoded at the W locus of the mouse. , 1990, Development.

[15]  A. Bradley,et al.  Multiple defects and perinatal death in mice deficient in follistatin , 1995, Nature.

[16]  A. Bradley,et al.  Genomic DNA microextraction: a method to screen numerous samples. , 1992, Analytical biochemistry.

[17]  M. Matzuk.  Functional analysis of mammalian members of the transforming growth factor-β superfamily , 1995, Trends in Endocrinology & Metabolism.

[18]  R. Jaenisch,et al.  Functional analysis of activins during mammalian development , 1995, Nature.

[19]  E. Huang,et al.  The expression pattern of the c-kit ligand in gonads of mice supports a role for the c-kit receptor in oocyte growth and in proliferation of spermatogonia. , 1993, Developmental biology.

[20]  B. Vanderhyden,et al.  Developmental pattern of the secretion of cumulus expansion-enabling factor by mouse oocytes and the role of oocytes in promoting granulosa cell differentiation. , 1990, Developmental biology.

[21]  A. Bradley,et al.  Different phenotypes for mice deficient in either activins or activin receptor type II , 1995, Nature.

[22]  R. Jaenisch,et al.  Activin/inhibin beta B subunit gene disruption leads to defects in eyelid development and female reproduction. , 1994, Genes & development.

[23]  G. Borsani,et al.  Structure of the mouse growth/differentiation factor 9 gene. , 1994, Biochimica et biophysica acta.

[24]  E. Robertson.  Teratocarcinomas and embryonic stem cells : a practical approach , 1987 .

[25]  Y. Taketani,et al.  Fas/APO-1/CD95 system as a mediator of granulosa cell apoptosis in ovarian follicle atresia. , 1996, Endocrinology.