Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis
Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis
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DOI：
10.1152/ajplung.2001.280.5.l1030
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发表时间：
2001-05-01
影响因子：
4.9
通讯作者：
Warburton, D
中科院分区：
文献类型：
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作者：
Shi, W;Zhao, JS;Warburton, D
骨形态发生蛋白4 （Bone morphogenetic protein-4, BMP-4）是胚胎肺发育的关键形态因子，在外周上皮中高水平表达，但BMP-4在早期小鼠肺分支形态发生中的作用调控机制尚不清楚。在这里，我们研究了BMP-4拮抗剂Gremlin，它是BMP拮抗剂DAN家族的一员，可以结合并阻断BMP-2/4的活性。胚胎小鼠肺中gremlin的表达水平在胚胎早期假腺期（胚胎日(E) 11.5-14.5）最高，在胎儿肺成熟期（E18.5至出生后第1天）降低。原位杂交显示gremlin在肺外周间质和上皮中弥漫性表达，但在E11.5时分枝芽和E16.5后大气道中有较高的上皮表达。在E11.5肺器官培养中，我们发现外源性BMP-4显著增强外周肺上皮分支形态发生，而内源性格莱姆林表达反义寡核苷酸的减少实现了与外源性BMP-4相同的功能获得表型，包括增加上皮细胞增殖和表面活性剂蛋白C的表达。另一方面，腺病毒过度表达gremlin可阻断外源性BMP-4的刺激作用。因此，我们的数据支持Gremlin在肺分支形态发生中是BMP-4生理负调节因子的假设。
Bone morphogenetic protein-4 (BMP-4) is a key morphogen for embryonic lung development that is expressed at high levels in the peripheral epithelium, but the mechanisms that modulate BMP-4 function in early mouse lung branching morphogenesis are unclear. Here, we studied the BMP-4 antagonist Gremlin, which is a member of the DAN family of BMP antagonists that can bind and block BMP-2/4 activity. The expression level of gremlin in embryonic mouse lungs is highest in the early embryonic pseudoglandular stage [embryonic days (E) 11.5-14.5] and is reduced during fetal lung maturation (E18.5 to postnatal day 1). In situ hybridization indicates that gremlin is diffusely expressed in peripheral lung mesenchyme and epithelium, but relatively high epithelial expression occurs in branching buds at E11.5 and in large airways after E16.5. In E11.5 lung organ culture, we found that exogenous BMP-4 dramatically enhanced peripheral lung epithelial branching morphogenesis, whereas reduction of endogenous gremlin expression with antisense oligonucleotides achieved the same gain-of-function phenotype as exogenous BMP-4, including increased epithelial cell proliferation and surfactant protein C expression. On the other hand, adenoviral overexpression of gremlin blocked the stimulatory effects of exogenous BMP-4. Therefore, our data support the hypothesis that Gremlin is a physiologically negative regulator of BMP-4 in lung branching morphogenesis.