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First published online 3 October 2007
doi: 10.1242/dev.009464

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Sulfated glycosaminoglycans are necessary for Nodal signal transmission from the node to the left lateral plate in the mouse embryo

Shinya Oki^1,*, Ryuju Hashimoto², Yuko Okui³, Michael M. Shen^4,, Eisuke Mekada⁵, Hiroki Otani², Yukio Saijoh^1,6 and Hiroshi Hamada^1,

¹ Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, and CREST, Japan Science and Technology Corporation (JST), 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
² Department of Developmental Biology, Center for Integrated Research in Science, Faculty of Medicine, Shimane University, 89-1 Enyacho, Izumo 693-8501, Japan.
³ Department of Biosignaling and Radioisotope Experiments, Center for Integrated Research in Science, Faculty of Medicine, Shimane University, 89-1 Enyacho, Izumo 693-8501, Japan.
⁴ Center for Advanced Biotechnology and Medicine and Department of Pediatrics, University of Medicine and Dentistry of New Jersey - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
⁵ Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁶ Department of Neurobiology and Anatomy, Program in Human Molecular Biology and Genetics, and The Eccles Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, UT 84112-5330, USA.

Author for correspondence (e-mail: hamada{at}fbs.osaka-u.ac.jp)

Accepted 20 August 2007

Situs-specific organogenesis in the mouse results from leftward fluid flow in the node cavity and subsequent left-sided expression of Nodal in the lateral plate mesoderm (LPM). Nodal expression at the node is essential for the subsequent asymmetric Nodal expression in the left LPM, but the precise role of Nodal produced at the node has remained unknown. We have now investigated how the Nodal signal is transferred from the node to the LPM. Externally supplied Nodal protein failed to signal to the LPM, suggesting that the Nodal signal is transferred to the LPM via an internal route rather than an external one. Transgenic rescue experiments showed that the Nodal co-receptor Cryptic (Cfc1) is required only in the LPM, not at the node, for asymmetric Nodal expression in the LPM, indicating that the Nodal signal is not relayed indirectly between the node and LPM. Nodal interacts in vitro with sulfated glycosaminoglycans (GAGs), which are specifically localized to the basement membrane-like structure between the node and LPM in the mouse embryo. Inhibition of sulfated GAG biosynthesis prevents Nodal expression in the LPM. These data suggest that Nodal produced at the node might travel directly to the LPM via interaction with sulfated GAGs.

Key words: Left-right asymmetry, Node, Nodal, Extracellular matrix, Glycosaminoglycan, Mouse

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