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Uterine Msx-1 and Wnt4 Signaling Becomes Aberrant in Mice with the Loss of Leukemia Inhibitory Factor or Hoxa-10: Evidence for a Novel Cytokine-Homeobox-Wnt Signaling in Implantation

Departments of Pediatrics (T.D., H.S., Y.G., S.K.Da., S.K.De.), Cell and Developmental Biology and Pharmacology (S.K.De.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; and Target Discovery and Department of Pharmacology (A.R., S.M.), NV Organon, 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Sudhansu K. Dey, Vanderbilt University Medical Center, Developmental Biology, MCN-D4100, Nashville, Tennessee 37232-2678. E-mail: sk.dey{at}vanderbilt.edu.

Successful implantation absolutely depends on the reciprocal interaction between the implantation-competent blastocyst and the receptive uterus. Expression and gene targeting studies have shown that leukemia inhibitory factor (LIF), a cytokine of the IL-6 family, and Hoxa-10, an abdominalB-like homeobox gene, are crucial to implantation and decidualization in mice. Using these mutant mice, we sought to determine the importance of Msx-1 (another homeobox gene formerly known as Hox-7.1) and of Wnt4 (a ligand of the Wnt family) signaling in implantation because of their reported functions during development. We observed that Msx-1, Wnt4, and a Wnt antagonist sFRP4 are differentially expressed in the mouse uterus during the periimplantation period, suggesting their role in implantation. In addition, we observed an aberrant uterine expression of Msx-1 and sFRP4 in Lif mutant mice, and of Wnt4 and sFRP4 in Hoxa-10 mutant mice, further reinforcing the importance of these signaling pathways in implantation. Collectively, the present results provide evidence for a novel cytokine-homeotic-Wnt signaling network in implantation.

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