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

Abstract

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.

Activation of PI3K signaling prevents aminoglycoside-induced hair cell death in the murine cochlea

“…In the inner ear, deletion of PTEN resulted in supernumerary hair cells that developed proper hair bundles ( Dong et al, 2010a ) presumably due to proliferation of hair cell progenitors ( Sun et al, 2014 ). In contrast, ablation of PTEN showed defects in spiral ganglion neuron fasciculation that may lead to apoptosis ( Dong et al, 2010b ; Kim et al, 2013 ). PI3K signaling has not been well studied in the aging or damaged cochlea.…”

Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss

“…For example, Pten loss causes the activation of Akt, which in turn activates mTORC1 signaling by inhibiting the Tsc1/Tsc2 complex (31). However, Pten ablation in NSE in the same Atoh1-Cre mice did not cause hearing loss in mice (34). Pten knockout in hair cells was recently reported to prevent gentamicin-induced hair cell death (35).…”

Patterns of Gene Expression Associated with Pten Deficiency in the Developing Inner Ear

“…Phosphatase and tensin homologue (PTEN), a lipid phosphatase, is negatively regulated by PI3K signaling and contributes to cellular processes including proliferation, differentiation and migration [11] – [14] . Many studies have investigated the function of Pten loss in mice, which causes profound alterations in the regulation of cellular maintenance in a cell-type specific manner in various organs [15] – [17] . Recently, we characterized the phenotype of inner-ear-specific Pten conditional knockout (cKO) mice, which demonstrated abnormal phenotypes (e.g., ectopic hair cells in the cochlear sensory epithelium and neuronal defects) [15] .…”

“…Many studies have investigated the function of Pten loss in mice, which causes profound alterations in the regulation of cellular maintenance in a cell-type specific manner in various organs [15] – [17] . Recently, we characterized the phenotype of inner-ear-specific Pten conditional knockout (cKO) mice, which demonstrated abnormal phenotypes (e.g., ectopic hair cells in the cochlear sensory epithelium and neuronal defects) [15] . In particular, mouse inner ear lacking Pten had neuronal deficits such as disorganized nerve fibers with apoptosis of spiral ganglion.…”