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MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons.

Larimore J, Ryder PV, Kim KY, Ambrose LA, Chapleau C, Calfa G, Gross C, Bassell GJ, Pozzo-Miller L, Smith Y, Talbot K, Park IH, Faundez V - PLoS ONE (2013)

Bottom Line: In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients.Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice.Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Agnes Scott College, Decatur, Georgia, USA.

ABSTRACT
Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.

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MeCP2 Regulates mRNA Levels of BLOC1-Interacting Proteins.BLOC1-interacting proteins were compiled from previous reports and mapped using the GeneGo Metacore pathway. The network was visualized in Cytoscope. Node sizes and colors were mapped to mRNA expression level changes in MECP2-overexpressing (A, Mecp2Tg/y) and Mecp2  mouse (B, Mecp2−/y) neurons as reported in Chahrour et al., 2008 [29]. We observed that six components of the BLOC1 interactome were modified by Mecp2 gene dosage. The protein products of three of these affected genes, PLDN, COG7, and PRDX1, are decreased in mice  for the schizophrenia susceptibility factor dysbindin [37].
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pone-0065069-g001: MeCP2 Regulates mRNA Levels of BLOC1-Interacting Proteins.BLOC1-interacting proteins were compiled from previous reports and mapped using the GeneGo Metacore pathway. The network was visualized in Cytoscope. Node sizes and colors were mapped to mRNA expression level changes in MECP2-overexpressing (A, Mecp2Tg/y) and Mecp2 mouse (B, Mecp2−/y) neurons as reported in Chahrour et al., 2008 [29]. We observed that six components of the BLOC1 interactome were modified by Mecp2 gene dosage. The protein products of three of these affected genes, PLDN, COG7, and PRDX1, are decreased in mice for the schizophrenia susceptibility factor dysbindin [37].

Mentions: The similarities between ASD and schizophrenia could result from a gene product affected in ASD. Such a gene could in turn modify the expression of proteins associated with pathways implicated in schizophrenia. We tested this hypothesis by investigating if the expression of genes encoding components of the dysbindin protein interaction network is susceptible to MeCP2 levels. We built a comprehensive dysbindin network by merging our dysbindin protein interaction network of 24 candidates with a prioritized list of putative protein-protein interactions for BLOC-1 subunits [37], [55]. The resultant dysbindin network contained 119 proteins. Six of these dysbindin interactome components were common to gene products whose mRNA expression is sensitive to Mecp2 content as previously determined by microarrays (Fig. 1) [29]. Pallidin (Pldn), peroxiredoxin 1 (Prdx1), COG7, pleiotrophin (PTN), ADP-ribosylation factor interacting protein 2 (ARFIP2), huntingtin-associated protein 1 (HAP1), and discoidin domain receptor tyrosine kinase 1 (DDR1) mRNAs are increased in MECP2 over-expressing mouse neurons (Fig. 1A, Mecp2Tg/y) and decreased in Mecp2- mouse neurons (Fig. 1B, Mecp2−/y). We previously demonstrated that three of these six proteins, pallidin, peroxiredoxin 1, and COG7, interact with dysbindin and their brain expression is sensitive to a dysbindin- allele (Bloc1s8sdy/sdy previously referred as Dtnbp1sdy/sdy) [37]. Our bioinformatic analysis suggests that MeCP2 regulates expression of key components of the dysbindin interaction network.


MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons.

Larimore J, Ryder PV, Kim KY, Ambrose LA, Chapleau C, Calfa G, Gross C, Bassell GJ, Pozzo-Miller L, Smith Y, Talbot K, Park IH, Faundez V - PLoS ONE (2013)

MeCP2 Regulates mRNA Levels of BLOC1-Interacting Proteins.BLOC1-interacting proteins were compiled from previous reports and mapped using the GeneGo Metacore pathway. The network was visualized in Cytoscope. Node sizes and colors were mapped to mRNA expression level changes in MECP2-overexpressing (A, Mecp2Tg/y) and Mecp2  mouse (B, Mecp2−/y) neurons as reported in Chahrour et al., 2008 [29]. We observed that six components of the BLOC1 interactome were modified by Mecp2 gene dosage. The protein products of three of these affected genes, PLDN, COG7, and PRDX1, are decreased in mice  for the schizophrenia susceptibility factor dysbindin [37].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672180&req=5

pone-0065069-g001: MeCP2 Regulates mRNA Levels of BLOC1-Interacting Proteins.BLOC1-interacting proteins were compiled from previous reports and mapped using the GeneGo Metacore pathway. The network was visualized in Cytoscope. Node sizes and colors were mapped to mRNA expression level changes in MECP2-overexpressing (A, Mecp2Tg/y) and Mecp2 mouse (B, Mecp2−/y) neurons as reported in Chahrour et al., 2008 [29]. We observed that six components of the BLOC1 interactome were modified by Mecp2 gene dosage. The protein products of three of these affected genes, PLDN, COG7, and PRDX1, are decreased in mice for the schizophrenia susceptibility factor dysbindin [37].
Mentions: The similarities between ASD and schizophrenia could result from a gene product affected in ASD. Such a gene could in turn modify the expression of proteins associated with pathways implicated in schizophrenia. We tested this hypothesis by investigating if the expression of genes encoding components of the dysbindin protein interaction network is susceptible to MeCP2 levels. We built a comprehensive dysbindin network by merging our dysbindin protein interaction network of 24 candidates with a prioritized list of putative protein-protein interactions for BLOC-1 subunits [37], [55]. The resultant dysbindin network contained 119 proteins. Six of these dysbindin interactome components were common to gene products whose mRNA expression is sensitive to Mecp2 content as previously determined by microarrays (Fig. 1) [29]. Pallidin (Pldn), peroxiredoxin 1 (Prdx1), COG7, pleiotrophin (PTN), ADP-ribosylation factor interacting protein 2 (ARFIP2), huntingtin-associated protein 1 (HAP1), and discoidin domain receptor tyrosine kinase 1 (DDR1) mRNAs are increased in MECP2 over-expressing mouse neurons (Fig. 1A, Mecp2Tg/y) and decreased in Mecp2- mouse neurons (Fig. 1B, Mecp2−/y). We previously demonstrated that three of these six proteins, pallidin, peroxiredoxin 1, and COG7, interact with dysbindin and their brain expression is sensitive to a dysbindin- allele (Bloc1s8sdy/sdy previously referred as Dtnbp1sdy/sdy) [37]. Our bioinformatic analysis suggests that MeCP2 regulates expression of key components of the dysbindin interaction network.

Bottom Line: In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients.Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice.Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Agnes Scott College, Decatur, Georgia, USA.

ABSTRACT
Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.

Show MeSH
Related in: MedlinePlus