The goya mutation identifies distinct novel roles for MAP3K1 in cochlear sensory hair cell development and survival
| Autor: | Susan Morse, Michael R. Bowl, George Nicholson, Emma L. Coghill, Steve D.M. Brown, Ian J. Jackson, Rachel E. Hardisty-Hughes, Sally H. Cross, Andrew Parker |
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| Rok vydání: | 2015 |
| Předmět: |
Genetics
0303 health sciences Cell type Cell growth Hearing loss 030305 genetics & heredity Mutant Neuroscience (miscellaneous) Medicine (miscellaneous) Heterozygote advantage Cell migration Biology medicine.disease General Biochemistry Genetics and Molecular Biology Cell biology 03 medical and health sciences medicine.anatomical_structure Immunology and Microbiology (miscellaneous) otorhinolaryngologic diseases medicine Sensorineural hearing loss sense organs medicine.symptom Spiral ganglion 030304 developmental biology |
| Zdroj: | Disease Models & Mechanisms. |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.023176 |
| Popis: | The Mitogen-Activated Protein kinase, MAP3K1, plays an important role in a number of cellular processes, including epithelial migration during eye organogenesis. In addition, studies in keratinocytes indicate that MAP3K1 signaling through JNK is important for actin stress fibre formation and cell migration. However, MAP3K1 can also act independently of JNK in the regulation of cell proliferation and apoptosis. We have identified a mouse mutant, goya, which exhibits eyes-open-at-birth and microphthalmia phenotypes. In addition, these mice also have hearing loss. The goya mice carry a splice site mutation in the Map3k1 gene. We show that goya and kinase-deficient Map3k1 homozygotes initially develop supernumerary cochlear outer hair cells (OHCs) that subsequently degenerate, and a progressive profound hearing loss is observed by 9-weeks of age. Heterozygote mice also develop supernumerary OHCs, but no cellular degeneration or hearing loss is observed. MAP3K1 is expressed in a number of inner ear cell types, including outer and inner hair cells, stria vascularis and spiral ganglion. Investigation of targets downstream of MAP3K1 identified an increase in p38 phosphorylation (Thr180/Tyr182) in multiple cochlear tissues. We also show the extra OHCs do not arise from aberrant control of proliferation via p27KIP1. The identification of the goya mutant reveals a novel signaling molecule involved with hair cell development and survival. Mammalian hair cells do not have the ability to regenerate after damage, which can lead to irreversible sensorineural hearing loss. Given the observed goya phenotype, and the many diverse cellular processes MAP3K1 is known to act upon, further investigation of this model may help elaborate upon the mechanisms underlying sensory hair cell specification, and pathways important for their survival. In addition, MAP3K1 is revealed as a new candidate gene for human sensorineural hearing loss. |
| Databáze: | OpenAIRE |
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