SMAD1/5 Signaling in the Early Equine Placenta Regulates Trophoblast Differentiation and Chorionic Gonadotropin Secretion

Endocrinology - Tập 155 Số 8 - Trang 3054-3064 - 2014
Victoria Cabrera-Sharp1, Jordan E. Read1, Stephanie Richardson1, Alycia A. Kowalski1, Douglas F. Antczak2, Judith E. Cartwright3, Abir Mukherjee1, Amanda M. de Mestre1
1Comparative Biomedical Sciences (V.C-S., J.E.R., S.R., A.A.K., A.M., A.M.d.M.), The Royal Veterinary College, London NW1 0TU, United Kingdom
2Baker Institute for Animal Health (D.F.A.), College of Veterinary Medicine, Cornell University, Ithaca, New York 14853
3Biomedical Sciences (J.E.C.), St George's University of London SW17 0RE, London, United Kingdom

Tóm tắt

TGFβ superfamily proteins, acting via SMAD (Sma- and Mad-related protein)2/3 pathways, regulate placental function; however, the role of SMAD1/5/8 pathway in the placenta is unknown. This study investigated the functional role of bone morphogenetic protein (BMP)4 signaling through SMAD1/5 in terminal differentiation of primary chorionic gonadotropin (CG)-secreting trophoblast. Primary equine trophoblast cells or placental tissues were isolated from day 27–34 equine conceptuses. Detected by microarray, RT-PCR, and quantitative RT-PCR, equine chorionic girdle trophoblast showed increased gene expression of receptors that bind BMP4. BMP4 mRNA expression was 20- to 60-fold higher in placental tissues adjacent to the chorionic girdle compared with chorionic girdle itself, suggesting BMP4 acts primarily in a paracrine manner on the chorionic girdle. Stimulation of chorionic girdle-trophoblast cells with BMP4 resulted in a dose-dependent and developmental stage-dependent increase in total number and proportion of terminally differentiated binucleate cells. Furthermore, BMP4 treatment induced non-CG-secreting day 31 chorionic girdle trophoblast cells to secrete CG, confirming a specific functional response to BMP4 stimulation. Inhibition of SMAD2/3 signaling combined with BMP4 treatment further enhanced differentiation of trophoblast cells. Phospho-SMAD1/5, but not phospho-SMAD2, expression as determined by Western blotting was tightly regulated during chorionic girdle trophoblast differentiation in vivo, with peak expression of phospho-SMAD1/5 in vivo noted at day 31 corresponding to maximal differentiation response of trophoblast in vitro. Collectively, these experiments demonstrate the involvement of BMP4-dependent pathways in the regulation of equine trophoblast differentiation in vivo and primary trophoblast differentiation in vitro via activation of SMAD1/5 pathway, a previously unreported mechanism of TGFβ signaling in the mammalian placenta.

Từ khóa


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Endocrinology

Tập 155 Số 8

3054-3064

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