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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-08-0563v1 202/3/419    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wang, Y. Articles by Farnworth, P. G PubMed PubMed Citation Articles by Wang, Y. Articles by Farnworth, P. G

¹ Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, Victoria 3168, Australia
² Department of Biochemistry, Monash University, Clayton, Victoria 3168, Australia
³ School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia 5005, Australia
⁴ Department of Obstetrics and Gynaecology
⁵ Department of Physiology, Monash University, Clayton, Victoria 3168, Australia

(Correspondence should be addressed to P Farnworth at Prince Henry's Institute of Medical Research; Email: paul.farnworth{at}princehenrys.org)

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 LβT2 gonadotrophs, and in mouse adrenal glands, particularly foetal and neonatal cortical cells. AC, LβT2, 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-β-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 LβT2 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.