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Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus

Abstract

The hedgehog family of morphogens are regulators of cell proliferation, differentiation and cell-cell communication. These morphogens have been shown to have important roles in organogenesis, spermatogenesis, stem cell maintenance and oncogenesis1,2,3,4,5,6,7,8,9. Indian hedgehog (encoded by Ihh) has been shown to be expressed in the uterine epithelium under the control of the steroid hormone, progesterone10,11. Although in vivo and in vitro studies have shown that progesterone achieves its effects on uterine function through epithelial-stromal cross-talk, molecular mediator(s) for this cellular communication pathway have not been elucidated12,13. Using new experimental approaches that ablate Ihh specifically in Pgr-positive uterine cells of the mouse, we demonstrate that Ihh is an essential mediator of Pgr action in the uterus, and expression of this factor is critical in mediating the communication between the uterine epithelium and stroma required for embryo implantation.

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Figure 1: The expression pattern of Ihh and genes regulated by Ihh in the mouse Ihhf/f and Ihhd/d uterus.
Figure 2: Implantation and decidualization in Ihhf/f and Ihhd/d mice.
Figure 3: Preimplantation and postimplantation phenotypes of Ihhf/f and Ihhd/d uteri.
Figure 4: Preimplantation gene expression in Ihhf/f and Ihhd/d uteri.

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Acknowledgements

We thank J. Li, B. Ngo, J. Li and J.L. DeMayo, M.S. for technical assistance; and H. Franco for manuscript preparation. This work was supported by the US National Institute of Child Health and Human Development and the US National Institutes of Health as part of the Cooperative Program on Trophoblast-Maternal Tissue Interactions (U01HD042311) (to F.J.D.); a Reproductive Biology Training Grant (5 T32 HD07165) (to K.L.); R01 DK45641 (to M.-J.T.); R01-DK55636 to (S.Y.T); RO1-CA77530, Department of Defense Breast Cancer Research Program IDEA Award DMAMD-17-01-0138 and the Susan G. Komen Award BCTR0503763 (to J.P.L.); a Volkswagen Foundation “Conditional Mutagenesis” grant and a grant from Roche Diagnostics and the Bavarian Ministry for Economic Affairs, Transport and Technology (to B.L.).

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Contributions

This study was designed by F.J.D., M.-J.T., S.T., J.P.L. and R.T. Phenotype assessment was performed by J.J., I.K. and C.-T.Y. Ihh floxed mice were generated by B.L. and D.W.S. PR-CRE mice were generated by J.P.L. SAG was provided by R.T. COUP-TFII reagents were provided by M.-J.T. and S.T. J.P.L. and F.J.D. contributed to the writing of the manuscript. F.J.D. is the primary principal investigator for this research.

Corresponding author

Correspondence to Francesco J DeMayo.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Embryo attachment in the Ihhf/f and Ihhd/d uterus. (PDF 2769 kb)

Supplementary Table 1

Primers used. (PDF 56 kb)

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Lee, K., Jeong, J., Kwak, I. et al. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet 38, 1204–1209 (2006). https://doi.org/10.1038/ng1874

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