FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination

• Published in: Nature 2005-05, Vol.435 (7039), p.172-177
• Main Authors: Hirokawa, Nobutaka, Tanaka, Yosuke, Okada, Yasushi
• Format: Article
• Language: English
• Subjects: Acids; Animals; Biological and medical sciences; Body Patterning - drug effects; Calcium - metabolism; Calcium Signaling - drug effects; Cilia - drug effects; Cilia - physiology; Embryo, Mammalian - cytology; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryology: invertebrates and vertebrates. Teratology; Embryonic growth stage; Fibroblast Growth Factor 8; Fibroblast Growth Factors - deficiency; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fluid flow; Fundamental and applied biological sciences. Psychology; Hedgehog Proteins; Humanities and Social Sciences; Mice; multidisciplinary; Organogenesis. Fetal development; Organogenesis. Physiological fonctions; Peptides; Receptors, Fibroblast Growth Factor - metabolism; Science; Science (multidisciplinary); Signal transduction; Trans-Activators - metabolism; Trans-Activators - pharmacology; Trans-Activators - secretion; Tretinoin - metabolism; Tretinoin - pharmacology; Vertebrates
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature03494

The precise specification of left–right asymmetry is an essential process for patterning internal organs in vertebrates. In mouse embryonic development, the symmetry-breaking process in left–right determination is initiated by a leftward extraembryonic fluid flow on the surface of the ventral node. However, it is not known whether the signal transduction mechanism of this flow is chemical or mechanical. Here we show that fibroblast growth factor (FGF) signalling triggers secretion of membrane-sheathed objects 0.3–5 µm in diameter termed ‘nodal vesicular parcels’ (NVPs) that carry Sonic hedgehog and retinoic acid. These NVPs are transported leftward by the fluid flow and eventually fragment close to the left wall of the ventral node. The silencing effects of the FGF-receptor inhibitor SU5402 on NVP secretion and on a downstream rise in Ca 2+ were sufficiently reversed by exogenous Sonic hedgehog peptide or retinoic acid, suggesting that FGF-triggered surface accumulation of cargo morphogens may be essential for launching NVPs. Thus, we propose that NVP flow is a new mode of extracellular transport that forms a left–right gradient of morphogens. No left or right turn Though symmetrical from the outside, the body plan of vertebrates and other animals is far from symmetrical inside. By the time the human heart and lung develop in the embryo they are directed to the left and right of the body cavity. Much research has gone into establishing the genetics and signalling mechanisms that impose this asymmetry. But there is a catch: some tissues, chiefly the muscles and skeleton, must ignore or overrule the instruction if they are not to become asymmetric. Three papers in this issue, and a News and Views piece by Eran Hornstein and Clifford J. Tabin, address the fascinating question of how the somites, embryonic elements that give rise to symmetrical tissues, pull off that trick.