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.
Highlights
In auditory system development, the otic placode undergoes invagination to form otocysts, which generate a complex membranous labyrinth and ganglia through a series of morphological events via harmonized coordination of various signaling molecules such as fibroblast growth factors, Notch, bone morphogenetic proteins, and Wnt [1,2,3,4,5]
Pten Expression Patterns during Inner Ear Development To evaluate the role of Pten during inner ear development, we examined the expression pattern of Pten from embryonic day (E)10.5 to E16.5 in the developing inner ear (Fig. 1)
At E10.5, Pten was expressed in the cochleovestibular ganglion (CVG) area but hardly detected in the inner ear epithelium (Fig. 1A, a–f)
Summary
In auditory system development, the otic placode undergoes invagination to form otocysts, which generate a complex membranous labyrinth and ganglia through a series of morphological events via harmonized coordination of various signaling molecules such as fibroblast growth factors, Notch, bone morphogenetic proteins, and Wnt [1,2,3,4,5]. The CVG complexes are separated into the spiral and the vestibular ganglia. Spiral ganglia undergo maturation processes around E11.5 to E15.5 (with a peak at E13.5) in a basal-to-apical innervation pattern [7]. The neurites of the spiral ganglia extend toward the developing sensory epithelium (i.e., Kolliker’s organ) under the guidance of neurotrophins such as brain-derived neurotrophic factor and neurotrophin-3 (NT-3) [8]. Because development of CVG neurons in the inner ear is complicated, involving a variety of developmentally regulated signaling pathways, the molecular mechanisms of spiral ganglia differentiation are not well understood
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