NDST1-dependent heparan sulfate regulates BMP signaling and internalization in lung development
NDST1-dependent heparan sulfate regulates BMP signaling and internalization in lung development
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DOI：
10.1242/jcs.034736
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发表时间：
2009-04-15
影响因子：
4
通讯作者：
Hu, Gengxi
中科院分区：
文献类型：
--
作者：
Hu, Zhonghua;Wang, Chaochen;Hu, Gengxi
硫酸乙酰肝素蛋白聚糖（HSPG）是多种信号传导途径所必需的，其中之一是骨形态发生蛋白（BMP）信号传导途径。N-脱乙酰基酶/N-磺基转移酶-1（NDST 1）参与合成HSPG的硫酸乙酰肝素（HS）链，并参与骨和肺的发育。在这里，我们报告，尽管Ndst 2，Ndst 3和Ndst 4基因的冗余表达，Ndst 1（-/-）小鼠显示肺细胞分化缺陷和细胞增殖增加。肺中Ndst 1的缺失增强了体内下游BMP信号传导。Noggin是BMP的拮抗剂，可以挽救外植体培养中Ndst 1（-/-）肺形态发生缺陷。进一步的体外研究表明，Ndst 1的缺失通过降低BMP与内源性HS的结合而显著损害BMP内化。外源性肝素可以挽救Ndst 1（-/-）肺中BMP信号传导和BMP内化异常。因此，我们认为HS通过控制BMP与HS结合之间的平衡来调节BMP信号传导，并且BMP受体和NDST 1依赖性修饰对该过程至关重要。结果表明，NDST 1依赖的HS是必不可少的BMP在胚胎肺发育的正常功能。
Heparan sulfate proteoglycans (HSPGs) are required for various signaling pathways, one of which is the bone morphogenetic protein (BMP) signaling pathway. N-deacetylase/N-sulfotransferase-1 (NDST1) participates in synthesizing heparan sulfate (HS) chains of HSPGs, and is involved in bone and lung development. Here, we report that in spite of the redundant expression of Ndst2, Ndst3 and Ndst4 genes, Ndst1(-/-) mice display defective differentiation of lung cells and increased cell proliferation. Loss of Ndst1 in the lung enhances downstream BMP signaling in vivo. Noggin, which is an antagonist of BMP, can rescue the Ndst1(-/-) lung morphogenetic defects in explant cultures. Further studies in vitro indicated that loss of Ndst1 significantly impairs BMP internalization by decreasing BMP binding to endogenous HS. Exogenous heparin can rescue both the BMP signaling and BMP internalization abnormalities in Ndst1(-/-) lung. Thus, we propose that HS regulates BMP signaling by controlling the balance between BMP binding to HS, and that BMP receptors and NDST1-dependent modification are essential for this process. The results suggest that NDST1-dependent HS is essential for proper functioning of BMP in embryonic lung development.