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Patterns of gene expression associated with Pten deficiency in the developing inner ear.

Kim HJ, Ryu J, Woo HM, Cho SS, Sung MK, Kim SC, Park MH, Park T, Koo SK - PLoS ONE (2014)

Bottom Line: We identified 46 statistically significant transcripts using significance analysis of microarrays, with the false-discovery rate set at 0%.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).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of Health, Chungcheongbuk-do, South Korea.

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.

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Expression patterns of Spp1 and Rgs4 during inner ear development.Expression levels of Spp1 (A, B) and Rgs4 (C, D) were examined by in situ hybridization at E14.5. Both Spp1 and Rgs4 expression were observed in SGNs. Consistent with the microarray results, expression levels of Spp1 and Rgs4 were increased in the Pten cKO compared to wild-type mice. Scale bars: 100 µm.
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pone-0097544-g002: Expression patterns of Spp1 and Rgs4 during inner ear development.Expression levels of Spp1 (A, B) and Rgs4 (C, D) were examined by in situ hybridization at E14.5. Both Spp1 and Rgs4 expression were observed in SGNs. Consistent with the microarray results, expression levels of Spp1 and Rgs4 were increased in the Pten cKO compared to wild-type mice. Scale bars: 100 µm.

Mentions: In particular, changed expression levels of several genes were detected in the Pten-deficient SGNs; i.e., Pvalb, Spp1, and Rgs4. We found that the levels of Pvalb, a neuronal marker [32], were downregulated (Fig. S1E, F). Reduced levels of Pvalb expression may be explained by the loss of Pvalb-expressing neurons in Pten-deficient mice. We observed increased levels of Spp1 (also known as osteopontin, Opn) and Rgs4 expression in Pten-deficient SGNs compared to the wild-type (Fig. 2). In the cochlea and vestibular dark cells, Spp1 may be responsible for regulation of ions in the inner ear fluid. The role of Spp1 in SGNs may be associated with regulation of nitric oxide production, which is considered to be associated with auditory neurotransmission in adenosine triphosphate (ATP)-induced Ca2+ signaling [33], [34]. Functionally, several lines of evidence have shown that Spp1 may play a role in neurodegeneration [35], [36]. Upregulation of SPP1 was detected in lesions or within the cerebral or spinal fluid in patients with neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. Spp1-knockout mice showed reduced neurodegeneration induced by MPTP [37]. Following crush injury to the optic nerve, strongly expressed Spp1 by macrophages may have inhibitory effects on axon growth [38]. Therefore, inhibition of axon outgrowth described in Pten cKO mice (i.e., shortened length of spiral ganglion toward the modiolus) may be at least partly explained by the dysregulation of Spp1 expression in SGNs.


Patterns of gene expression associated with Pten deficiency in the developing inner ear.

Kim HJ, Ryu J, Woo HM, Cho SS, Sung MK, Kim SC, Park MH, Park T, Koo SK - PLoS ONE (2014)

Expression patterns of Spp1 and Rgs4 during inner ear development.Expression levels of Spp1 (A, B) and Rgs4 (C, D) were examined by in situ hybridization at E14.5. Both Spp1 and Rgs4 expression were observed in SGNs. Consistent with the microarray results, expression levels of Spp1 and Rgs4 were increased in the Pten cKO compared to wild-type mice. Scale bars: 100 µm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4043736&req=5

pone-0097544-g002: Expression patterns of Spp1 and Rgs4 during inner ear development.Expression levels of Spp1 (A, B) and Rgs4 (C, D) were examined by in situ hybridization at E14.5. Both Spp1 and Rgs4 expression were observed in SGNs. Consistent with the microarray results, expression levels of Spp1 and Rgs4 were increased in the Pten cKO compared to wild-type mice. Scale bars: 100 µm.
Mentions: In particular, changed expression levels of several genes were detected in the Pten-deficient SGNs; i.e., Pvalb, Spp1, and Rgs4. We found that the levels of Pvalb, a neuronal marker [32], were downregulated (Fig. S1E, F). Reduced levels of Pvalb expression may be explained by the loss of Pvalb-expressing neurons in Pten-deficient mice. We observed increased levels of Spp1 (also known as osteopontin, Opn) and Rgs4 expression in Pten-deficient SGNs compared to the wild-type (Fig. 2). In the cochlea and vestibular dark cells, Spp1 may be responsible for regulation of ions in the inner ear fluid. The role of Spp1 in SGNs may be associated with regulation of nitric oxide production, which is considered to be associated with auditory neurotransmission in adenosine triphosphate (ATP)-induced Ca2+ signaling [33], [34]. Functionally, several lines of evidence have shown that Spp1 may play a role in neurodegeneration [35], [36]. Upregulation of SPP1 was detected in lesions or within the cerebral or spinal fluid in patients with neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. Spp1-knockout mice showed reduced neurodegeneration induced by MPTP [37]. Following crush injury to the optic nerve, strongly expressed Spp1 by macrophages may have inhibitory effects on axon growth [38]. Therefore, inhibition of axon outgrowth described in Pten cKO mice (i.e., shortened length of spiral ganglion toward the modiolus) may be at least partly explained by the dysregulation of Spp1 expression in SGNs.

Bottom Line: We identified 46 statistically significant transcripts using significance analysis of microarrays, with the false-discovery rate set at 0%.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).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.

View Article: PubMed Central - PubMed

Affiliation: Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of Health, Chungcheongbuk-do, South Korea.

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.

Show MeSH
Related in: MedlinePlus