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Development. 2017 Jul 1;144(13):2392-2401. doi: 10.1242/dev.149757. Epub 2017 Jun 2.

Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling.

Author information

1
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
2
Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
3
Department of Plastic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
4
Department of Biochemistry, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
5
Department of Cardiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
6
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
7
Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
8
Departments of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine of Yeshiva University, 1301 Morris Park Avenue, Price Center 420, Bronx, NY 10461, USA.
9
Karlsruhe Institute of Technology (KIT), Zoological Institute, Cell- and Neurobiology, Fritz-Haber-Weg 4, Karlsruhe 76131, Germany.
10
Department of Organ and Tissue Anatomy, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
11
Department Molecules - Signaling - Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, Martinsried 82152, Germany.
12
Munich Cluster for Systems Neurology (Synergy), Munich 80336, Germany.
13
Department of Medicine, Program in Molecular Medicine, VA Salt Lake City Health Care System, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
14
Department of Oncological Sciences, VA Salt Lake City Health Care System, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
15
Department of Human Genetics, VA Salt Lake City Health Care System, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
16
ARUP Laboratories, VA Salt Lake City Health Care System, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
17
Division of Cardiovascular Medicine, Department of Medicine, VA Salt Lake City Health Care System, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
18
Department of Cardiology, VA Salt Lake City Health Care System, University of Utah, 15 North 2030 East, Salt Lake City, UT 84112, USA.
19
Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu 610072, China.
20
Department of Organ and Tissue Anatomy, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan ykubo33@a3.keio.jp yamagish@hama-med.ac.jp.
21
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan ykubo33@a3.keio.jp yamagish@hama-med.ac.jp.

Abstract

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.

KEYWORDS:

Angiogenesis; FLRT2; Neurovascular; Placenta; UNC5B

PMID:
28576770
DOI:
10.1242/dev.149757
[Indexed for MEDLINE]
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