The goya mutation identifies distinct novel roles for MAP3K1 in cochlear sensory hair cell development and survival

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.

MAP3K1 function is essential for cyto-architecture of mouse organ of Corti and survival of auditory hair cells

“…In a parallel study, a splice-site mutation in the Map3k1 gene in goya mutant mice was identified as part of an ENU mutagenesis screening program ( Parker et al, 2015 ). g oya mice also exhibit a progressive hearing-loss phenotype along with the supernumerary OHCs.…”

“…g oya mice also exhibit a progressive hearing-loss phenotype along with the supernumerary OHCs. Interestingly, when maintained on the same genetic background (C3H), the goya and Map3k1 tm1Yxia mutant mice were found to have a similar progressive hearing-loss phenotype and were profoundly deaf by 9 weeks ( Parker et al, 2015 ). Modulation of the phenotype of a given allele by the genetic background of an inbred strain is a well-documented phenomenon ( Doetschman, 2009 ; Montagutelli, 2000 ).…”

Mechanism of Sex Determination in Humans: Insights from Disorders of Sex Development

“…XY Map3k1 mPHD/+ mice that are heterozygous for an inactive PHD motif have a significantly enlarged testes but with a reduced number of Leydig cells [Charlaftis et al, 2014]. Another Map3k1 mouse model, goya , exhibits a severe hearing loss [Parker et al, 2015]. This data suggest that in testis determination either the MAP kinase signaling pathways in human or mouse have diverged or the difference in phenotype is caused by an intrinsic difference in the type of mutation.…”

Deficit of mitogen-activated protein kinase phosphatase 1 (DUSP1) accelerates progressive hearing loss

“…Our data point to the activation of MAPK14 as the possible link between the absence of DUSP1 and a premature increase in cochlear oxidative stress and pro-inflammatory status. MAPK14 is expressed in the cochlea (Parker et al, 2015; Sanchez-Calderon et al, 2010) and it is activated at different time points after noise insult (Jamesdaniel et al, 2011; Maeda et al, 2013; Murillo-Cuesta et al, 2015), as well as during ageing (Sha et al, 2009). We show here that DUSP1 is induced by noise-exposure and that its transcription increases with age.…”

“…JNK and p38 MAPK transcripts and proteins are expressed in the cochlea from late intrauterine development (Parker et al, 2015; Sanchez-Calderon et al, 2010). They form part of the adult cochlear response to noise insult (Jamesdaniel et al, 2011; Maeda et al, 2013) and to ageing (Sha et al, 2009).…”