PTEN attenuates PIP3/Akt signaling in the cochlea of the aging CBA/J mouse

Sha, Su Hua; Chen, Fu Quan; Schacht, Jochen

doi:10.1016/j.heares.2009.09.002

Cited by 39 publications

(33 citation statements)

References 34 publications

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“…The decreased levels of p-Akt (S473) in OHCs after exposure to PTS noise are in accordance with early reports that p-Akt (S473) levels decrease after aminoglycoside treatment or with aging (Jiang et al 2006;Chung et al 2006;Haake et al 2009;Sha et al 2010). However, the levels of p-Akt (S473) increase in whole cochlear homogenates according to Western blot analysis, implicating another cochlear cell type in response to PTS noise stress.…”

Section: Discussionsupporting

confidence: 90%

“…For example, aminoglycoside treatment results in permanent hearing loss and sensory hair cell loss, and phosphorylation of Akt on serine 473 (p-Akt S473) in sensory hair cells is decreased by such treatment (Jiang et al 2006). A decrease in p-Akt (S473) in sensory hair cells is also involved in age-related hearing impairment (Sha et al 2010). On the other hand, Akt has been implicated as an integral part of the protein kinase C (PKC) pathway that promotes spiral ganglion neuron survival (Lallemend et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling

Chen

Talaska

et al. 2015

JARO

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The PI3K/Akt signaling pathway is involved in mediating survival of sensory hair cells. Here, we investigated the involvement of PI3K/Akt in noise-induced hearing loss in both temporary and permanent threshold shift noise models. The PI3K regulatory subunit p85α and phosphorylation of Akt on serine 473 (p-Akt S473) are downregulated in sensory hair cells, including both outer and inner hair cells, and supporting cells of the mouse organ of Corti 1 h after exposure to permanent-threshold-shift-inducing noise (PTS noise), but not with temporary-threshold-shiftinducing noise (TTS noise). In contrast, the PI3K catalytic subunit p110α and phosphorylation of Akt on threonine 308 (p-Akt T308) do not change with PTS or TTS noise. Additionally, mice pretreated with p85α small interfering RNA (siRNA) have decreased expression of p-Akt1 (S473) in their sensory hair cells and increased sensitivity to TTS noise-induced hearing loss. Finally, Akt1-knockout mice also have enhanced sensitivity to TTS noise-induced hearing loss. In conclusion, this study suggests that endogenous PI3K/Akt signaling is an intrinsic protective mechanism of the inner ear. Blockade of PI3K/Akt signaling pathways increases sensitivity to TTS noise-induced hearing loss.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling

Chen

Talaska

et al. 2015

JARO

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“…CBA/J mice do have variable levels of age related hearing loss (Sha, et al, 2008). The RNA used in this study came from mice that had retained relatively good ABR thresholds up to 18 months of age (Sha, Chen, & Schacht, 2010). We can only speculate that isoform p1 is more important in development in the mouse and isoform p2 is more important in the adult murine inner ear.…”

Section: Discussionmentioning

confidence: 99%

Age-related changes in expression of CTL2/SLC44A2 and its isoforms in the mouse inner ear

et al. 2011

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The membrane glycoprotein CTL2/SLC44A2 is expressed by supporting cells in the inner ear and has been identified as a target of antibodies that may induce auto-immune hearing loss. To determine if CTL2/SLC44A2 also has roles in inner ear development and to distinguish between isoform-specific roles, we assessed age-related changes in expression of CTL2/SLC44A2 isoforms and protein in the developing murine inner ear. We determined that both isoform p1 and isoform p2 (named for the upstream p1 and proximal p2 promoters that control alternate exons 1a and 1b) were robustly expressed as early as E14 and persisted during embryonic development, but after birth the p1 isoform fell to barely detectable levels while isoform p2 levels were maintained. This trend continued and became even more apparent later in post-natal development and remained in mature ears until at least 6 weeks of age. In aged (18mo old) mice, the level of isoform p1 transcripts rose again to levels similar to the p2 isoform like that seen early in development. At the earliest stage examined, CTL2/SLC44A2 protein was expressed in both immature supporting cells and immature sensory cells, but after birth expression in the sensory cells declined in both the utricle and cochlea and by day P1 expression of CTL2/SLC44A2 was restricted to supporting cells. The changes we observed in isoform distribution are indicative of differential developmental roles and age related changes between the two isoforms of CTL2/SLC44A2 in the inner ear.

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“…These results indicate that Pten may participate in regulating neural organization, connection, and outgrowth, including neurodevelopment. In the inner ear, it has been reported that Pten expression is observed in the developing cochlea and that phosphorylated Pten accumulates in hair cell and supporting cell nuclei of the aging cochlea [27], [28]. Despite extensive studies of Pten- null phenotypes in various systems, little is known about the neuronal roles and mechanisms of Pten during inner ear development.…”

Section: Introductionmentioning

confidence: 99%

Conditional Deletion of Pten Leads to Defects in Nerve Innervation and Neuronal Survival in Inner Ear Development

et al. 2013

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All cellular phenomena and developmental events, including inner ear development, are modulated through harmonized signaling networks. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is a major signaling component involved in cross talk with key regulators of development; i.e., Wnt, Notch, and bone morphogenetic proteins. Although Pten function has been studied in various systems, its role in inner ear development is poorly understood. Here, we used inner ear-specific Pten conditional knockout mice and examined the characteristics of the inner ear. In a detailed analysis of the phenotype, reduced cochlear turning and widened epithelia were observed. Phalloidin staining of sensory epithelium revealed that hair cell patterns were disturbed; i.e., additional rows of hair cells were discovered. The neural abnormality revealed a reduction in and disorganization of nerve fibers, including apoptosis at the neural precursor stage. Pten deficiency induced increased phosphorylation of Akt at Ser473. The elevation of inhibitory glycogen synthase kinase 3β Ser9 phosphorylation (pGSK3β) was sustained until the neuronal differentiation stage at embryonic day 14.5, instead of pGSK3β downregulation. This is the first report on the influence of Pten/Akt/GSK3β signaling on the development of spiral ganglia. These results suggest that Pten is required for the maintenance of neuroblast number, neural precursors, and differentiation in the inner ear.

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PTEN attenuates PIP3/Akt signaling in the cochlea of the aging CBA/J mouse

Cited by 39 publications

References 34 publications

Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling

Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling

Age-related changes in expression of CTL2/SLC44A2 and its isoforms in the mouse inner ear

Conditional Deletion of Pten Leads to Defects in Nerve Innervation and Neuronal Survival in Inner Ear Development

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