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

Abstract

In inner ear development, phosphatase and tensin homolog (PTEN) is necessary for neuronal maintenance, such as neuronal survival and accurate nerve innervations of hair cells. We previously reported that Pten conditional knockout (cKO) mice exhibited disorganized fasciculus with neuronal apoptosis in spiral ganglion neurons (SGNs). To better understand the genes and signaling networks related to auditory neuron maintenance, we compared the profiles of differentially expressed genes (DEGs) using microarray analysis of the inner ear in E14.5 Pten cKO and wild-type mice. We identified 46 statistically significant transcripts using significance analysis of microarrays, with the false-discovery rate set at 0%. Among the DEGs, expression levels of candidate genes and expression domains were validated by quantitative real-time RT-PCR and in situ hybridization, respectively. Ingenuity pathway analysis using DEGs identified significant signaling networks associated with apoptosis, cellular movement, and axon guidance (i.e., secreted phosphoprotein 1 (Spp1)-mediated cellular movement and regulator of G-protein signaling 4 (Rgs4)-mediated axon guidance). This result was consistent with the phenotypic defects of SGNs in Pten cKO mice (e.g., neuronal apoptosis, abnormal migration, and irregular nerve fiber patterns of SGNs). From this study, we suggest two key regulatory signaling networks mediated by Spp1 and Rgs4, which may play potential roles in neuronal differentiation of developing auditory neurons.

Osteopontin deficiency ameliorates Alport pathology by preventing tubular metabolic deficits

“…Pharmacological inhibition of OPN in Col4a3 -/mice rather than genetic deletion is needed to determine the effects of OPN blockade on hearing in the Alport mice without the bias of genetic background, especially given that C57BL6 mice develop hearing deficits earlier in life (25,26). Our potentially novel finding on the role of OPN in hearing function supports the result of a microarray screen from the inner ears of developing PTEN-knockout mice, which suggested a role for OPN signaling in neuronal differentiation of developing auditory neurons (62).…”

Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

“…RGS proteins are not widely studied in the auditory system. Among more than 20 RGS proteins, only RGS4 is expressed in SGNs 18 , supporting cells and OC of adult cochlea. Increased level of RGS4 is associated with neuronal defects in PTEN-deficient SGNs 18 .…”

“…Several GPCRs also exert otoprotection. For example, adenosine A 1 receptors 14 – 16 and cannabinoid receptor 2 12 , 17 are expressed in the cochlea, predominantly in the organ of Corti (OC), strial vascularis (SVA) and spiral ganglion neurons (SGN) 12 , 14 , 18 . Activation of these GPCRs reduced inflammation, oxidative stress and reduced cisplatin-induced ABR threshold shifts 12 , 14 , 19 .…”

Gene expression profiling of the inner ear

“…A microarray analysis of the inner ear at E14.5 confirmed deregulation of networks of genes involved in these processes (Kim et al. ).…”

“…Mouse mutants lacking the lipid phosphatase PTEN also show defects in spiral ganglion neurons, such as irregular migration of nerve fibres and apoptosis . A microarray analysis of the inner ear at E14.5 confirmed deregulation of networks of genes involved in these processes (Kim et al 2014).…”