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A Grhl2-dependent gene network controls trophoblast branching morphogenesis.

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      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.

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      Affiliations
      [1 ] Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany Experimental and Clinical Research Center, a collaboration between the Max Delbrück Center and the Medical Faculty of the Charité, Robert-Rössle-Str. 10, Berlin 13125, Germany.
      [2 ] Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany Experimental and Clinical Research Center, a collaboration between the Max Delbrück Center and the Medical Faculty of the Charité, Robert-Rössle-Str. 10, Berlin 13125, Germany Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
      [3 ] Experimental and Clinical Research Center, a collaboration between the Max Delbrück Center and the Medical Faculty of the Charité, Robert-Rössle-Str. 10, Berlin 13125, Germany.
      [4 ] Department of Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Children's Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA.
      [5 ] Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD)/National Institutes of Health (NIH), 5 Research Court, Rockville, MD 20850, USA.
      [6 ] Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany.
      [7 ] Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
      [8 ] Bioinformatics, Max Planck Institute for Biology of Ageing, Robert-Koch-Str. 21, Cologne 50931, Germany.
      [9 ] Department of Gynecology and Obstetrics, Institute of Clinical Medicine, Oslo University Hospital and University of Oslo, Kirkeveien 166, Oslo 0450, Norway.
      [10 ] Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany Department of Urology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany Berlin Institute of Urologic Research, Berlin 10117, Germany.
      [11 ] Department of Pathology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany.
      [12 ] Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany Experimental and Clinical Research Center, a collaboration between the Max Delbrück Center and the Medical Faculty of the Charité, Robert-Rössle-Str. 10, Berlin 13125, Germany Department of Nephrology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany kai.schmidt-ott@mdc-berlin.de.
      Journal
      Development
      Development (Cambridge, England)
      1477-9129
      0950-1991
      Mar 15 2015
      : 142
      : 6
      142/6/1125
      10.1242/dev.113829
      25758223
      © 2015. Published by The Company of Biologists Ltd.
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