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Dis Model Mech. 2015 Dec;8(12):1555-68. doi: 10.1242/dmm.023176. Epub 2015 Nov 5.

The goya mouse mutant reveals distinct newly identified roles for MAP3K1 in the development and survival of cochlear sensory hair cells.

Author information

1
MRC Mammalian Genetics Unit, MRC Harwell, Oxford, OX11 0RD, UK.
2
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK.
3
MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Edinburgh, EH4 2XU, UK The Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG, UK.
4
MRC Mammalian Genetics Unit, MRC Harwell, Oxford, OX11 0RD, UK Department of Statistics, University of Oxford, Oxford, OX1 3TG, UK.
5
MRC Mammalian Genetics Unit, MRC Harwell, Oxford, OX11 0RD, UK s.brown@har.mrc.ac.uk.

Abstract

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 signalling 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 the 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 that the extra OHCs do not arise from aberrant control of proliferation via p27KIP1. The identification of the goya mutant reveals a signalling 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 that MAP3K1 is known to act upon, further investigation of this model might help to 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.

KEYWORDS:

Cochlear development; Hearing loss; MAP3K1; Sensory hair cell survival; Supernumerary outer hair cells

PMID:
26542706
PMCID:
PMC4728324
DOI:
10.1242/dmm.023176
[Indexed for MEDLINE]
Free PMC Article

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