Katharina Walentin 1 , Christian Hinze 1 , Max Werth 2 , Nadine Haase 3 , Saaket Varma 4 , Robert Morell 5 , Annekatrin Aue 1 , Elisabeth Pötschke 6 , David Warburton 4 , Andong Qiu 7 , Jonathan Barasch 7 , Bettina Purfürst 6 , Christoph Dieterich 8 , Elena Popova 6 , Michael Bader 6 , Ralf Dechend 3 , Anne Cathrine Staff 9 , Zeliha Yesim Yurtdas 10 , Ergin Kilic 11 , Kai M Schmidt-Ott 12
Mar 15 2015
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:||Basement membrane defects, Spint1, Placenta defects, Epithelial morphogenesis, Epithelial differentiation|