Interrelationship of growth differentiation factor 9 and inhibin in early folliculogenesis and ovarian tumorigenesis in mice.
To investigate the interrelationship of inhibin alpha and growth differentiation factor 9 (GDF9) during early folliculogenesis, we generated mice lacking both inhibin alpha and GDF9. Our findings on these Inha Gdf9 double-mutant mice are as follows: 1). females develop ovarian tumors and a cachexia-like wasting syndrome, resembling mice lacking inhibin alpha alone. This indicates that the granulosa cells are competent to proliferate despite the lack of GDF9; 2). follicular development progresses to multiple-layer follicle stages before tumorigenesis. This demonstrates that the up-regulation of inhibin alpha in the Gdf9 knockout ovary directly prevents the proliferation of the granulosa cells at the primary follicle stage, an effect that is released in the absence of inhibin alpha; 3). a morphological theca forms around the preantral follicles with no detectable selective theca markers [i.e. 17alpha-hydroxylase (Cyp17), LH receptor (Lhr), and Kit]. These results indicate that the theca recruitment can occur independently of GDF9, but the differentiation of thecal cells is blocked; and 4). inhibin/activin subunits betaA, betaB, and Kit ligand (Kitl) mRNA are highly up-regulated, suggesting that the increased activins and KITL play functional roles in early folliculogenesis. Thus, GDF9 appears to function indirectly to regulate early granulosa cell proliferation and theca recruitment in vivo.
Wu
Xuemei
X
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Chen
Lei
L
Brown
Christopher A
CA
Yan
Changning
C
Matzuk
Martin M
MM
D028341:Activins / Q000737:chemistry; D000818:Animals; D055430:Bone Morphogenetic Protein 15; D002100:Cachexia / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism; D055429:Growth Differentiation Factor 9; D018398:Homeodomain Proteins; D017403:In Situ Hybridization; D007265:Inhibins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000378:metabolism; D006080:Ovarian Follicle / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000378:metabolism; D054339:Steroidogenic Factor 1; D013799:Theca Cells / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D019282:Wasting Syndrome / Q000235:genetics
C525901:BMP15 protein, human; C525902:Bmp15 protein, mouse; D055430:Bone Morphogenetic Protein 15; D004268:DNA-Binding Proteins; C525897:GDF9 protein, human; C525898:Gdf9 protein, mouse; D055429:Growth Differentiation Factor 9; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C082631:NR5A2 protein, human; D015513:Oncogene Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D019089:Stem Cell Factor; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D028341:Activins; D007265:Inhibins; D012313:RNA; D019009:Proto-Oncogene Proteins c-kit