Haque Khujista, Pandey Atul K, Zheng Hong-Wei, Riazuddin Saima, Sha Su-Hua, Puligilla Chandrakala
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, and.
Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland 21201.
J Neurosci. 2016 Jan 27;36(4):1347-61. doi: 10.1523/JNEUROSCI.1853-15.2016.
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.
Sensory hair cells (HCs) are the mechanoreceptors within the inner ear responsible for our sense of hearing. HCs are formed before birth, and mammals lack the ability to restore the sensory deficits associated with their loss. In this study, we show, for the first time, that MEKK4 signaling is essential for the development of normal cytoarchitecture and hearing function as MEKK4 signaling-deficient mice exhibit a significant reduction of HCs and a hearing loss. We also identify MEKK4 as a critical hub kinase for FGF20-FGFR1 signaling to induce HC differentiation in the mammalian cochlea. These results reveal a new paradigm in the regulation of HC differentiation and provide significant new insights into the mechanism of Fgf signaling governing HC formation.
位于内耳的机械感觉毛细胞（HCs）对于听力和平衡至关重要。发育过程中增殖、感觉特异性和分化的精确协调对于确保耳蜗和前庭上皮中HCs的正确模式至关重要。最近的研究表明，FGF20信号对于适当的HC分化至关重要。然而，FGF20信号促进HC分化的机制仍不清楚。在这里，我们表明丝裂原活化蛋白3激酶4（MEKK4）的表达在内耳发育过程中受到高度调控，并且对于正常的细胞结构和功能至关重要。纯合激酶失活MEKK4突变的小鼠表现出明显的听力损失。体内缺乏MEKK4活性也导致耳蜗和前庭HCs数量显著减少，这表明MEKK4活性对于内耳中HCs的整体发育至关重要。此外，我们表明体内FGF20信号的丧失会抑制MEKK4活性，而Fgf20功能的增强会刺激MEKK4表达，这表明Fgf20调节MEKK4活性以调节细胞分化。最后，我们首次证明，MEKK4作为一个关键节点整合FGF20-FGFR1信号反应，以特异性影响HC发育，并且通过激活MEKK4的FGFR1信号对于外毛细胞分化是必需的。总的来说，这项研究提供了令人信服的证据，证明MEKK4在内耳形态发生中起着重要作用，并确定了MEKK4表达在调节HC发育过程中FGFR1的特异性反应以及FGF20/FGFR1信号激活MEKK4以实现正常感觉细胞分化方面的必要性。
感觉毛细胞（HCs）是内耳中的机械感受器，负责我们的听觉。HCs在出生前形成，哺乳动物缺乏恢复与它们丧失相关的感觉缺陷的能力。在这项研究中，我们首次表明，MEKK4信号对于正常细胞结构和听力功能的发育至关重要，因为MEKK4信号缺陷的小鼠表现出HCs显著减少和听力损失。我们还确定MEKK4是FGF20-FGFR1信号在哺乳动物耳蜗中诱导HC分化的关键枢纽激酶。这些结果揭示了HC分化调控的新范式，并为Fgf信号控制HC形成的机制提供了重要的新见解。
