Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling

Ikue Tai-Nagara, Yusuke Yoshikawa, Naoko Numata, Tomofumi Ando, Keisuke Okabe, Yuki Sugiura, Masaki Ieda, Nobuyuki Takakura, Osamu Nakagawa, Bin Zhou, Koji Okabayashi, Makoto Suematsu, Yuko Kitagawa, Martin Bastmeyer, Kohji Sato, Rüdiger Klein, Sutip Navankasattusas, Dean Y. Li, Satoru Yamagishi, Yoshiaki Kubota

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


The placental labyrinth is the interface for gas and nutrient exchange between the embryo and the mother; hence its proper development is essential for embryogenesis. However, the molecular mechanism underlying development of the placental labyrinth, particularly in terms of its endothelial organization, is not well understood. Here, we determined that fibronectin leucine-rich transmembrane protein 2 (FLRT2), a repulsive ligand of the UNC5 receptor family for neurons, is unexpectedly expressed in endothelial cells specifically in the placental labyrinth. Mice lacking FLRT2 in endothelial cells exhibited embryonic lethality at mid-gestation, with systemic congestion and hypoxia. Although they lacked apparent deformities in the embryonic vasculature and heart, the placental labyrinths of these embryos exhibited aberrant alignment of endothelial cells, which disturbed the feto-maternal circulation. Interestingly, this vascular deformity was related to endothelial repulsion through binding to the UNC5B receptor. Our results suggest that the proper organization of the placental labyrinth depends on coordinated inter-endothelial repulsion, which prevents uncontrolled layering of the endothelium.

Original languageEnglish (US)
Pages (from-to)2392-2401
Number of pages10
JournalDevelopment (Cambridge)
Issue number13
StatePublished - 2017


  • Angiogenesis
  • FLRT2
  • Neurovascular
  • Placenta
  • UNC5B

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


Dive into the research topics of 'Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling'. Together they form a unique fingerprint.

Cite this