title: MEKK4 Signaling Regulates Sensory Cell Development and Function in the Mouse Inner Ear.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, and.
authors.forename: Khujista
authors.initials: K
authors.lastname: Haque
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, and.
authors.forename: Atul K
authors.initials: AK
authors.lastname: Pandey
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, and.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Zheng
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, Maryland 21201.
authors.forename: Saima
authors.identifier: http://orcid.org/0000-0002-8645-4761
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, and.
authors.forename: Su-Hua
authors.initials: SH
authors.lastname: Sha
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, and puligill@musc.edu.
authors.forename: Chandrakala
authors.identifier: http://orcid.org/0000-0003-4474-1022
authors.initials: C
authors.lastname: Puligilla
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D007758:Ear, Inner / Q000166:cytology / Q000201:enzymology / Q000254:growth & development; D004622:Embryo, Mammalian; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006199:Hair Cells, Auditory, Inner / Q000502:physiology; D048768:MAP Kinase Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011247:Pregnancy; D012097:Repressor Proteins / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013136:Spiral Ganglion / Q000166:cytology; D014404:Tubulin / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D048768:MAP Kinase Kinase Kinase 4; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; D014404:Tubulin; C500943:Atoh1 protein, mouse; C405694:Hairy, HRT1 protein; C485778:Hey2 protein, mouse; C527783:Sox2 protein, mouse; C482780:Map3k4 protein, mouse
keywords: FGF20; MEKK4; cellular differentiation; cochlea; mouse
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