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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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Functional network analysis associated with Pten-deficient inner ear.Network analysis using the Ingenuity Pathway Analysis (IPA) software was conducted using selected genes that were differentially expressed and their close relationships. IPA results show two core networks consisted of Spp1-(red line) and Rgs4-associated interactions (blue line). Genes that were differentially expressed are indicated in pink, and predicted interacting genes (not contained in the microarray data) are indicated in white. Axon guidance signaling pathway-related genes are outlined in magenta. Molecular interactions between connected genes represent direct (solid line) or indirect (dotted line) functional relationships based on the IPA database. Green indicates negative fold changes, while red denotes positive fold changes, according to color intensity.
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pone-0097544-g003: Functional network analysis associated with Pten-deficient inner ear.Network analysis using the Ingenuity Pathway Analysis (IPA) software was conducted using selected genes that were differentially expressed and their close relationships. IPA results show two core networks consisted of Spp1-(red line) and Rgs4-associated interactions (blue line). Genes that were differentially expressed are indicated in pink, and predicted interacting genes (not contained in the microarray data) are indicated in white. Axon guidance signaling pathway-related genes are outlined in magenta. Molecular interactions between connected genes represent direct (solid line) or indirect (dotted line) functional relationships based on the IPA database. Green indicates negative fold changes, while red denotes positive fold changes, according to color intensity.

Mentions: To examine signaling networks during neuronal maintenance in the Pten-deficient inner ear, networks were subjected to IPA analysis with 82 DEGs (FDR<0.05) (Fig. 3). IPA analysis identified significant biological functions, including auditory disease, cell death and survival, and cellular movement (data not shown). Auditory diseases included Otoa, Tectb, estrogen-related receptor beta (Esrrb), and solute carrier family 26 member 4 (Slc26A4), which may explain the functional defects of the developing inner ear. Cell death and survival-related genes were enriched, including phosphatase 2A regulatory subunit B beta2 (Ppp2r2b), S100 calcium-binding protein A8 (S100A8), S100A9, insulin-like growth factor-binding protein 7 (Igfbp7), and cathelicidin antimicrobial peptide (Camp).


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)

Functional network analysis associated with Pten-deficient inner ear.Network analysis using the Ingenuity Pathway Analysis (IPA) software was conducted using selected genes that were differentially expressed and their close relationships. IPA results show two core networks consisted of Spp1-(red line) and Rgs4-associated interactions (blue line). Genes that were differentially expressed are indicated in pink, and predicted interacting genes (not contained in the microarray data) are indicated in white. Axon guidance signaling pathway-related genes are outlined in magenta. Molecular interactions between connected genes represent direct (solid line) or indirect (dotted line) functional relationships based on the IPA database. Green indicates negative fold changes, while red denotes positive fold changes, according to color intensity.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0097544-g003: Functional network analysis associated with Pten-deficient inner ear.Network analysis using the Ingenuity Pathway Analysis (IPA) software was conducted using selected genes that were differentially expressed and their close relationships. IPA results show two core networks consisted of Spp1-(red line) and Rgs4-associated interactions (blue line). Genes that were differentially expressed are indicated in pink, and predicted interacting genes (not contained in the microarray data) are indicated in white. Axon guidance signaling pathway-related genes are outlined in magenta. Molecular interactions between connected genes represent direct (solid line) or indirect (dotted line) functional relationships based on the IPA database. Green indicates negative fold changes, while red denotes positive fold changes, according to color intensity.
Mentions: To examine signaling networks during neuronal maintenance in the Pten-deficient inner ear, networks were subjected to IPA analysis with 82 DEGs (FDR<0.05) (Fig. 3). IPA analysis identified significant biological functions, including auditory disease, cell death and survival, and cellular movement (data not shown). Auditory diseases included Otoa, Tectb, estrogen-related receptor beta (Esrrb), and solute carrier family 26 member 4 (Slc26A4), which may explain the functional defects of the developing inner ear. Cell death and survival-related genes were enriched, including phosphatase 2A regulatory subunit B beta2 (Ppp2r2b), S100 calcium-binding protein A8 (S100A8), S100A9, insulin-like growth factor-binding protein 7 (Igfbp7), and cathelicidin antimicrobial peptide (Camp).

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