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

Nature. 2005 May 12;435(7039):172-7. doi: 10.1038/nature03494.

Abstract

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 microm 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 Ca2+ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning* / drug effects
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Cilia / drug effects
  • Cilia / physiology*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / embryology*
  • Embryo, Mammalian / metabolism*
  • Fibroblast Growth Factor 8
  • Fibroblast Growth Factors / deficiency
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Hedgehog Proteins
  • Mice
  • Receptors, Fibroblast Growth Factor / metabolism
  • Trans-Activators / metabolism*
  • Trans-Activators / pharmacology
  • Tretinoin / metabolism*
  • Tretinoin / pharmacology

Substances

  • Fgf8 protein, mouse
  • Hedgehog Proteins
  • Receptors, Fibroblast Growth Factor
  • Trans-Activators
  • Fibroblast Growth Factor 8
  • Tretinoin
  • Fibroblast Growth Factors
  • Calcium