Document Detail

Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary.
MedLine Citation:
PMID:  10379899     Owner:  NLM     Status:  MEDLINE    
Growth differentiation factor-9 (GDF-9), a secreted member of the transforming growth factor-beta superfamily, is expressed at high levels in the mammalian oocyte beginning at the type 3a primary follicle stage. We have previously demonstrated that GDF-9-deficient female mice are infertile because of an early block in folliculogenesis at the type 3b primary follicle stage. To address the molecular defects that result from the absence of GDF-9, we have analyzed the expression of several important ovarian marker genes. The major findings of our studies are as follows: 1) There are no detectable signals around GDF-9-deficient follicles for several theca cell layer markers [i.e. 17alpha-hydroxylase, LH receptor (LHR), and c-kit, the receptor for kit ligand]. This demonstrates that in the absence of GDF-9, the follicles are incompetent to emit a signal that recruits theca cell precursors to surround the follicle; 2) The primary follicles of GDF-9-deficient mice demonstrate an up-regulation of kit ligand and inhibin-alpha. This suggests that these two important secreted growth factors, expressed in the granulosa cells, may be directly regulated in a paracrine fashion by GDF-9. Up-regulation of kit ligand, via signaling through c-kit on the oocyte, may be directly involved in the increased size of GDF-9-deficient oocytes and the eventual demise of the oocyte; 3) After loss of the oocyte, the cells of the GDF-9-deficient follicles remain in a steroidogenic cluster that histologically resembles small corpora lutea. However, at the molecular level, these cells are positive for both luteal markers (e.g. LHR and P-450 side chain cleavage) and nonluteal markers (e.g. inhibin alpha and P-450 aromatase). This demonstrates that initially the presence of the oocyte prevents the expression of luteinized markers, but that the absence of GDF-9 at an early timepoint alters the differentiation program of the granulosa cells; and 4) As demonstrated by staining with either proliferating cell nuclear antigen (PCNA) or Ki-67 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) labeling, the granulosa cells of GDF-9-deficient type 3b primary follicles fail to proliferate but also fail to undergo cell death. This suggests that granulosa cells of type 3b follicles require GDF-9 for continued growth and also to become competent to undergo apoptosis, possibly through a differentiation event Thus, these studies have enlightened us as to the paracrine roles of GDF-9 as well as the normal steps of granulosa cell and theca cell growth and differentiation within ovarian follicles.
J A Elvin; C Yan; P Wang; K Nishimori; M M Matzuk
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  13     ISSN:  0888-8809     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  1999 Jun 
Date Detail:
Created Date:  1999-08-03     Completed Date:  1999-08-03     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1018-34     Citation Subset:  IM    
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
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MeSH Terms
Aromatase / metabolism
Bone Morphogenetic Protein 15
Cell Cycle
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / metabolism
Cyclooxygenase 2
Estrogen Receptor beta
Glycoproteins / metabolism
Growth Differentiation Factor 9
Growth Substances / deficiency*,  genetics,  metabolism*
In Situ Nick-End Labeling
Inhibins / metabolism
Intercellular Signaling Peptides and Proteins*
Isoenzymes / metabolism
Mice, Inbred Strains
Microfilament Proteins / metabolism
Muscle Proteins*
Ovarian Follicle / metabolism*,  pathology*
Ovary / metabolism*
Peptides / metabolism
Prostaglandin-Endoperoxide Synthases / metabolism
Proto-Oncogene Proteins c-kit / metabolism
Receptors, Estrogen / metabolism
Receptors, FSH / metabolism
Receptors, LH / metabolism
Stem Cell Factor / metabolism
Theca Cells / cytology
Transforming Growth Factor beta / metabolism
Grant Support
Reg. No./Substance:
0/Bmp15 protein, mouse; 0/Bone Morphogenetic Protein 15; 0/Cdkn1a protein, mouse; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Estrogen Receptor beta; 0/Follistatin; 0/Gdf9 protein, mouse; 0/Glycoproteins; 0/Growth Differentiation Factor 9; 0/Growth Substances; 0/Intercellular Signaling Peptides and Proteins; 0/Isoenzymes; 0/Microfilament Proteins; 0/Muscle Proteins; 0/Peptides; 0/Receptors, Estrogen; 0/Receptors, FSH; 0/Receptors, LH; 0/Stem Cell Factor; 0/Tagln protein, mouse; 0/Transforming Growth Factor beta; 0/inhibin-alpha subunit; 104625-48-1/Activins; 57285-09-3/Inhibins; EC; EC 2; EC Synthases; EC Proteins c-kit

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