A Shh/miR-206/BDNF cascade coordinates innervation and formation of airway smooth muscle.
A Shh/miR-206/BDNF cascade coordinates innervation and formation of airway smooth muscle.
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DOI：
10.1523/jneurosci.2745-11.2011
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发表时间：
2011-10-26
期刊：
影响因子：
--
通讯作者：
Ai X
中科院分区：
文献类型：
--
作者：
Radzikinas K;Aven L;Jiang Z;Tran T;Paez-Cortez J;Boppidi K;Lu J;Fine A;Ai X
气道平滑肌（ASM）的神经控制功能障碍与炎症性疾病（如哮喘）有关。然而，肺中的神经发生知之甚少。本研究使用小鼠模型来研究ASM神经支配的发育机制，这是一个与肺分支形态发生过程中ASM形成高度协调的过程。我们表明，脑源性神经营养因子（BDNF）是一个重要的ASM衍生的神经支配信号。虽然BDNF mRNA表达与ASM形成和神经支配暂时分离，但BDNF蛋白通过miR-206的转录后抑制协同产生。使用化学和遗传方法的组合来调节音刺猬（Shh）信号传导，这是肺分支和ASM形成所必需的途径，我们表明Shh信号传导阻断miR-206表达，这反过来又增加BDNF蛋白表达。总之，我们的工作揭示了一个功能级联，涉及Shh，miR-206和BDNF协调ASM形成和神经支配。
Dysfunctional neural control of airway smooth muscle (ASM) is involved in inflammatory diseases, such as asthma. However, neurogenesis in the lung is poorly understood. This study uses mouse models to investigate developmental mechanisms of ASM innervation, a process that is highly coordinated with ASM formation during lung branching morphogenesis. We show that brain-derived neurotrophic factor (BDNF) is an essential ASM-derived signal for innervation. Although BDNF mRNA expression is temporally dissociated with ASM formation and innervation, BDNF protein is coordinately produced through post-transcriptional suppression by miR-206. Using a combination of chemical and genetic approaches to modulate sonic hedgehog (Shh) signaling, a pathway essential for lung branching and ASM formation, we show that Shh signaling blocks miR-206 expression, which in turn increases BDNF protein expression. Together, our work uncovers a functional cascade that involves Shh, miR-206 and BDNF to coordinate ASM formation and innervation.