MAP3K1 function is essential for cytoarchitecture of the mouse organ of Corti and survival of auditory hair cells.
MAP3K1 is a serine/threonine kinase that is activated by a diverse set of stimuli and exerts its effect through various downstream effecter molecules, including JNK, ERK1/2 and p38. In humans, mutant alleles of MAP3K1 are associated with 46,XY sex reversal. Until recently, the only phenotype observed in Map3k1(tm1Yxia) mutant mice was open eyelids at birth. Here, we report that homozygous Map3k1(tm1Yxia) mice have early-onset profound hearing loss accompanied by the progressive degeneration of cochlear outer hair cells. In the mouse inner ear, MAP3K1 has punctate localization at the apical surface of the supporting cells in close proximity to basal bodies. Although the cytoarchitecture, neuronal wiring and synaptic junctions in the organ of Corti are grossly preserved, Map3k1(tm1Yxia) mutant mice have supernumerary functional outer hair cells (OHCs) and Deiters' cells. Loss of MAP3K1 function resulted in the downregulation of Fgfr3, Fgf8, Fgf10 and Atf3 expression in the inner ear. Fgfr3, Fgf8 and Fgf10 have a role in induction of the otic placode or in otic epithelium development in mice, and their functional deficits cause defects in cochlear morphogenesis and hearing loss. Our studies suggest that MAP3K1 has an essential role in the regulation of these key cochlear morphogenesis genes. Collectively, our data highlight the crucial role of MAP3K1 in the development and function of the mouse inner ear and hearing.
Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Rizwan
R
Yousaf
Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
Qinghang
Q
Meng
Divisions of Pediatric Ophthalmology and Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.
Robert B
RB
Hufnagel
Department of Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
Ying
Y
Xia
Department of Pathology & Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Chandrakala
C
Puligilla
Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Zubair M
ZM
Ahmed
Department of Otorhinolaryngology Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA sriazuddin@smail.umaryland.edu.
Saima
S
Riazuddin
D000818:Animals; D001309:Auditory Threshold; D064652:Basal Bodies / Q000378:metabolism; D002470:Cell Survival; D015536:Down-Regulation / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018072:Hair Cells, Auditory, Outer / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D034381:Hearing Loss / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D021381:Protein Transport; D015398:Signal Transduction / Q000235:genetics; D013136:Spiral Ganglion / Q000473:pathology; D003689:Vestibular Nucleus, Lateral / Q000473:pathology
D005346:Fibroblast Growth Factors; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse
FGF signaling pathway; Fgf10; Fgf8; Fgfr3; Hearing loss; MAPK pathway; Map3k1; Mekk1; Supernumerary outer hair cells