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SMAD1/5 signaling in the early equine placenta regulates trophoblast differentiation and chorionic gonadotropin secretion

Cabrera-Sharp, V; Read, J E; Richardson, S; Kowalski, A A; Antczak, D F; Cartwright, J E; Mukherjee, A; De Mestre, A M


V Cabrera-Sharp

J E Read

S Richardson

A A Kowalski

D F Antczak

J E Cartwright

A Mukherjee

A M De Mestre


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.


Cabrera-Sharp, V., Read, J. E., Richardson, S., Kowalski, A. A., Antczak, D. F., Cartwright, J. E., …De Mestre, A. M. (2014). SMAD1/5 signaling in the early equine placenta regulates trophoblast differentiation and chorionic gonadotropin secretion. Endocrinology, 155(8), 3054-64.

Journal Article Type Article
Acceptance Date May 14, 2014
Publication Date Aug 1, 2014
Deposit Date Nov 11, 2014
Publicly Available Date Jul 5, 2018
Journal Endocrinology
Print ISSN 0013-7227
Publisher Endocrine Society
Peer Reviewed Peer Reviewed
Volume 155
Issue 8
Pages 3054-64
Public URL


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