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J. Biol. Chem., Vol. 282, Issue 43, 31725-31732, October 26, 2007

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Bone Morphogenetic Protein 2 Functions via a Conserved Signaling Pathway Involving Wnt4 to Regulate Uterine Decidualization in the Mouse and the Human^*

Quanxi Li, Athilakshmi Kannan, Wei Wang, Francesco J. DeMayo^¶, Robert N. Taylor^||, Milan K. Bagchi, and Indrani C. Bagchi¹

From the Departments of Veterinary Biosciences and Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802, the ^¶Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, and the ^||Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia 30322

A critical role of progesterone (P) during early pregnancy is to induce differentiation of the endometrial stromal cells into specialized decidual cells that support the development of the implanting embryo. The P-induced signaling pathways that participate in the formation and function of the decidual cells remain poorly understood. We report here that the expression of the bone morphogenetic protein 2 (BMP2), a morphogen belonging to the TGF superfamily, is induced downstream of P action in the mouse uterine stroma during decidualization. To determine the function of BMP2 during this differentiation process, we employed a primary culture system in which undifferentiated stromal cells isolated from pregnant mouse uterus undergo decidualization. When recombinant BMP2 was added to these stromal cultures, it markedly advanced the differentiation program. We also found that siRNA-mediated silencing of BMP2 expression in these cells efficiently blocked the differentiation process. Gene expression profiling experiments identified Wnt4 as a downstream target of BMP2 regulation in stromal cells undergoing decidualization. Attenuation of Wnt4 expression by siRNAs greatly reduced stromal differentiation in vitro, indicating that it is a key mediator of BMP2-induced decidualization. We also observed a remarkable induction in the expression of BMP2 in human endometrial stromal cells during decidualization in vitro in response to steroids and cAMP. Addition of BMP2 to these cultures led to a robust enhancement of Wnt4 expression and stimulated the differentiation process. Collectively, our studies uncovered a unique conserved pathway involving BMP2 and Wnt4 that mediates P-induced stromal decidualization in the mouse and the human.

Received for publication, June 8, 2007 , and in revised form, August 17, 2007.

^* This work was supported in part by National Institutes of Health Grants R01 HD-43381 (to I. C. B.) and R01 HD-44611 (to M. K. B.). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR16515-01 from the National Center for Research Resources, National Institutes of Health (to I. C. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Veterinary Biosciences, University of Illinois at Urbana-Champaign. Tel.: 217-333-7986; Fax: 217-244-1652; E-mail: ibagchi{at}uiuc.edu.

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