Extra-ovarian expression and activity of growth differentiation factor 9.

Growth differentiation factor 9 (GDF9) produced within the ovary plays an essential role during follicle maturation through actions on granulosa cells, but extra-ovarian expression, signalling and actions of GDF9 are less well characterised. The present studies confirm GDF9 expression in the mouse testis, pituitary gland and adrenocortical cancer (AC) cells, and establish its expression in L beta T2 gonadotrophs, and in mouse adrenal glands, particularly foetal and neonatal cortical cells. AC, L beta T2, TM3 Leydig and TM4 Sertoli cells express the requisite GDF9 binding signalling components, particularly activin receptor-like kinase (ALK) 5 and the bone morphogenetic protein (BMP)/GDF type II receptor, BMPRII (BMPR2). We therefore compared GDF9 activation of these potential extra-ovarian target cell types with its activation of granulosa cells. Recombinant mouse GDF9 stimulated expression of activin/transforming growth factor-beta-responsive reporters, pGRAS-luc or pAR3-lux, in TM4 and AC cells (IC50=145 ng/ml in the latter case), and two granulosa cell lines, KGN and COV434. The ALK4/5/7 inhibitor, SB431542, blocked GDF9 activity in each case. By contrast, GDF9 lacked specific effects on TM3 cells and rat primary pituitary and mouse L beta T2 gonadotrophs. Our findings show that GDF9 regulates the expression of R-SMAD2/3-responsive reporter genes through ALK4, 5 or 7 in extra-ovarian (adrenocortical and Sertoli) cells with similar potency and signalling pathway to its actions on granulosa cells, but suggest that expression of BMPRII, ALK5 (TGFBR1) and R-SMADs 2 and 3 may not be sufficient for a cell to respond to GDF9.

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