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A Grhl2-dependent gene network controls trophoblast branching morphogenesis

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Item Type:Article
Title:A Grhl2-dependent gene network controls trophoblast branching morphogenesis
Creators Name:Walentin, K. and Hinze, C. and Werth, M. and Haase, N. and Varma, S. and Morell, R. and Aue, A. and Pötschke, E. and Warburton, D. and Qiu, A. and Barasch, J. and Purfürst, B. and Dieterich, C. and Popova, E. and Bader, M. and Dechend, R. and Staff, A.C. and Yurtdas, Z.Y. and Kilic, E. and Schmidt-Ott, K.M.
Abstract:Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in pre-eclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branching morphogenesis. Selective Grhl2 inactivation only in epiblast-derived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIP-seq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2(-/-) placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction.
Keywords:Placenta Defects, Epithelial Differentiation, Epithelial Morphogenesis, Spint1, Basement Membrane Defects
Publisher:Company of Biologists
Page Range:1125-1136
Date:15 March 2015
Official Publication:https://doi.org/10.1242/dev.113829
PubMed:View item in PubMed

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