MEKK4 Signaling Regulates Sensory Cell Development and Function in the Mouse Inner Ear
MEKK4 Signaling Regulates Sensory Cell Development and Function in the Mouse Inner Ear
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DOI：
10.1523/jneurosci.1853-15.2016
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发表时间：
2016-01-27
影响因子：
5.3
通讯作者：
Puligilla, Chandrakala
中科院分区：
文献类型：
--
作者：
Haque, Khujista;Pandey, Atul K.;Puligilla, Chandrakala
内耳中的机械感觉毛细胞（HC）对听力和平衡至关重要。在发育过程中，精确协调增殖、感觉特异性和分化对于确保耳蜗和前庭上皮中HC的正确模式至关重要。最近的研究表明，FGF 20信号传导对于适当的HC分化至关重要。然而，FGF 20信号传导促进HC分化的机制仍然未知。在这里，我们表明，丝裂原活化蛋白3激酶4（MEKK 4）的表达是高度调节内耳发育过程中，是至关重要的正常细胞结构和功能。激酶失活MEKK 4突变的纯合子小鼠表现出显著的听力损失。体内缺乏MEKK 4活性也导致耳蜗和前庭HC数量的显著减少，表明MEKK 4活性对于内耳内HC的整体发育至关重要。此外，我们发现体内FGF 20信号传导的丧失抑制MEKK 4活性，而Fgf 20功能的获得刺激MEKK 4表达，表明Fgf 20调节MEKK 4活性以调节细胞分化。最后，我们首次证明，MEKK 4作为一个关键节点，整合FGF 20-FGFR 1信号传导反应，以特异性地影响HC的发育，并且通过激活MEKK 4的FGFR 1信号传导是外毛细胞分化所必需的。总的来说，这项研究提供了令人信服的证据，MEKK 4在内耳形态发生中的重要作用，并确定了MEKK 4表达在HC发育过程中调节FGFR 1特异性反应的需要，以及FGF 20/FGFR 1信号转导激活MEKK 4用于正常感觉细胞分化。
Mechanosensory hair cells (HCs) residing in the inner ear are critical for hearing and balance. Precise coordination of proliferation, sensory specification, and differentiation during development is essential to ensure the correct patterning of HCs in the cochlear and vestibular epithelium. Recent studies have revealed that FGF20 signaling is vital for proper HC differentiation. However, the mechanisms by which FGF20 signaling promotes HC differentiation remain unknown. Here, we show that mitogen-activated protein 3 kinase 4 (MEKK4) expression is highly regulated during inner ear development and is critical to normal cytoarchitecture and function. Mice homozygous for a kinase-inactive MEKK4 mutation exhibit significant hearing loss. Lack of MEKK4 activity in vivo also leads to a significant reduction in the number of cochlear and vestibular HCs, suggesting that MEKK4 activity is essential for overall development of HCs within the inner ear. Furthermore, we show that loss of FGF20 signaling in vivo inhibits MEKK4 activity, whereas gain of Fgf20 function stimulates MEKK4 expression, suggesting that Fgf20 modulates MEKK4 activity to regulate cellular differentiation. Finally, we demonstrate, for the first time, that MEKK4 acts as a critical node to integrate FGF20-FGFR1 signaling responses to specifically influence HC development and that FGFR1 signaling through activation of MEKK4 is necessary for outer hair cell differentiation. Collectively, this study provides compelling evidence of an essential role for MEKK4 in inner ear morphogenesis and identifies the requirement of MEKK4 expression in regulating the specific response of FGFR1 during HC development and FGF20/FGFR1 signaling activated MEKK4 for normal sensory cell differentiation.