FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination
FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination
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DOI：
10.1038/nature03494
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发表时间：
2005-05-12
期刊：
影响因子：
64.8
通讯作者：
Hirokawa, N
中科院分区：
文献类型：
--
作者：
Tanaka, Y;Okada, Y;Hirokawa, N
左右不对称性的精确描述是脊椎动物内部器官形成模式的一个重要过程。在小鼠胚胎发育中，左右决定的破膜过程是由腹结表面的胚外液流启动的。然而，目前尚不清楚这种流动的信号转导机制是化学的还是机械的。在这里，我们表明，成纤维细胞生长因子（FGF）信号触发分泌膜鞘的对象0.3 - 5 μ m的直径被称为“结节囊泡包裹”（NVP），携带音速刺猬和视黄酸。这些NVP被流体流动逆向运输，并最终在腹侧结的左壁附近破碎。FGF受体抑制剂SU 5402对NVP分泌和下游Ca 2+升高的沉默作用被外源性Sonic hedgehog肽或视黄酸充分逆转，表明FGF触发的货物形态发生素的表面积累可能是启动NVP所必需的。因此，我们认为NVP流是一种新的细胞外转运模式，形成了形态发生素的左右梯度。
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 mu m 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.