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Valerie Matagne - One of the best experts on this subject based on the ideXlab platform.
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correcting deregulated fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in mecp2 deficient male mice
Brain Research, 2018Co-Authors: Valerie Matagne, Matthew Frerking, Sarojini S Budden, Joyce Wondolowski, Nicholas A Delamere, Mohammad Shahidullah, Ursula S. Sandau, Sergio R. OjedaAbstract:Abstract Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxyd1 can rescue these RTT deficits, we studied the male progeny of Fxyd1 null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxyd1 allele, suggesting that NKA activity is under Fxyd1 inhibitory control. Deletion of one Fxyd1 allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxyd1 failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxyd1 in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth.
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Correcting deregulated Fxydl expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice
Brain Research, 2018Co-Authors: Valerie Matagne, Matthew Frerking, Sarojini S Budden, Joyce Wondolowski, Nicholas A Delamere, Mohammad Shahidullah, Ursula S. Sandau, Sergio R. OjedaAbstract:Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxydl may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxydl can rescue these RTT deficits, we studied the male progeny of Fxydl null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxydl allele, suggesting that NKA activity is under Fxydl inhibitory control. Deletion of one Fxydl allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxydl failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxydl in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth. (C) 2018 Elsevier B.V. All rights reserved.
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correcting deregulated fxyd1 expression ameliorates a behavioral impairment in a mouse model of rett syndrome
Brain Research, 2013Co-Authors: Valerie Matagne, Sarojini S Budden, Jacob Raber, Sergio R. OjedaAbstract:Abstract Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2. Several genes have been shown to be MECP2 targets. We previously identified FXYD1 (encoding phospholemman; a protein containing the motif phenylalanine-X-tyrosine-aspartate), a gene encoding a transmembrane modulator of the Na, K-ATPase (NKA) enzyme, as one of them. In the absence of MECP2, FXYD1 expression is increased in the frontal cortex (FC) of both RTT patients and Mecp2Bird null mice. Here, we show that Fxyd1 mRNA levels are also increased in the FC and hippocampus (HC) of male mice carrying a truncating mutation of the Mecp2 gene (Mecp2308). To test the hypothesis that some of the behavioral phenotypes seen in these Mecp2 mutants could be ameliorated by genetically preventing the Fxyd1 response to MECP2 deficiency, we crossed Fxyd1 null male mice with Mecp2308 heterozygous females and behaviorally tested the adult male offspring. Mecp2308 mice had impaired HC-dependent novel location recognition, and this impairment was rescued by deletion of both Fxyd1 alleles. No other behavioral or sensorimotor impairments were rescued. These results indicate that reducing FXYD1 levels improves a specific cognitive impairment in MECP2-deficient mice.
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brain region specific expression of fxyd1 an mecp2 target gene is regulated by epigenetic mechanisms
Journal of Neuroscience Research, 2011Co-Authors: Fatima Banine, Valerie Matagne, Larry S Sherman, Sergio R. OjedaAbstract:Fxyd1 encodes a trans-membrane protein that modulates Na+,K+-ATPase activity and is a substrate for multiple protein kinases. Fxyd1 expression is repressed by methyl CpG-binding protein 2 (Mecp2) in the frontal cortex (FC) but not in the cerebellum (CB) of the mouse brain. Consistently with these observations, FXYD1 mRNA abundance is increased in the FC of Rett syndrome (RTT) patients with MECP2 mutations. Because Fxyd1 is implicated in the regulation of neuronal excitability, understanding how Fxyd1 expression is controlled is important. Here we report that basal expression of Fxyd1a and Fxyd1b, the two main alternatively spliced forms of Fxyd1 mRNA, is lower in the FC than in the CB. This difference is accompanied by increased Mecp2 recruitment to the promoter region of these two Fxyd1 mRNA forms. DNA methylation of both promoters is more frequent in the FC than in the CB, and in both cases the most frequently methylated CpG dinucleotides are adjacent to [A/T]4 sequences required for high-affinity Mecp2 binding. Consistently with these features of epigenetic silencing, histone 3 acetylated at lysines 9 and 14 (H3K9/14ac) and histone 3 methylated at lysine 4 (H3K4me3), both activating histone marks, were associated with the Fxyd1 promoter to a lesser degree in the FC than in the CB. These results indicate that differential Fxyd1 expression in these two brain regions is, at least in part, regulated by an epigenetic mechanism involving increased DNA methylation of the two alternative Fxyd1 promoters, enhanced Mecp2 recruitment, and reduced association of activating histones. © 2011 Wiley-Liss, Inc.
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fxyd1 a modulator of na k atpase activity facilitates female sexual development by maintaining gonadotrophin releasing hormone neuronal excitability
Journal of Neuroendocrinology, 2009Co-Authors: Cecilia Garciarudaz, Valerie Matagne, Vivianne Deng, Oline K. Rønnekleiv, Martha A Bosch, Alan K Percy, Sergio R. OjedaAbstract:: The excitatory tone to gonadotrophin-releasing hormone (GnRH) neurones is a critical component underlying the pubertal increase in GnRH secretion. However, the homeostatic mechanisms modulating the response of GnRH neurones to excitatory inputs remain poorly understood. A basic mechanism of neuronal homeostasis is the Na(+),K(+)-ATPase-dependent restoration of Na(+) and K(+) transmembrane gradients after neuronal excitation. This activity is reduced in a mouse model of Rett syndrome (RTT), a neurodevelopmental disorder in which expression of FXYD1, a modulator of Na(+),K(+)-ATPase activity, is increased. We now report that the initiation, but not the completion of puberty, is advanced in girls with RTT, and that, in rodents, FXYD1 may contribute to the neuroendocrine regulation of female puberty by modulating GnRH neuronal excitability. Fxyd1 mRNA abundance reaches maximal levels in the female rat hypothalamus by the fourth postnatal week of life (i.e., around the time when the mode of GnRH secretion acquires an adult pattern of release). Although Fxyd1 mRNA expression is low in the hypothalamus, approximately 50% of GnRH neurones contain Fxyd1 transcripts. Whole-cell patch recording of GnRH-EGFP neurones revealed that the neurones of Fxyd1-null female mice respond to somatic current injections with a lower number of action potentials than wild-type cells. Both the age at vaginal opening and at first oestrous were delayed in Fxyd1(-/-) mice, but adult reproductive capacity was normal. These results suggest that FXYD1 contributes to facilitating the advent of puberty by maintaining GnRH neuronal excitability to incoming transsynaptic stimulatory inputs.
Sergio R. Ojeda - One of the best experts on this subject based on the ideXlab platform.
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correcting deregulated fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in mecp2 deficient male mice
Brain Research, 2018Co-Authors: Valerie Matagne, Matthew Frerking, Sarojini S Budden, Joyce Wondolowski, Nicholas A Delamere, Mohammad Shahidullah, Ursula S. Sandau, Sergio R. OjedaAbstract:Abstract Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxyd1 can rescue these RTT deficits, we studied the male progeny of Fxyd1 null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxyd1 allele, suggesting that NKA activity is under Fxyd1 inhibitory control. Deletion of one Fxyd1 allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxyd1 failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxyd1 in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth.
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Correcting deregulated Fxydl expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice
Brain Research, 2018Co-Authors: Valerie Matagne, Matthew Frerking, Sarojini S Budden, Joyce Wondolowski, Nicholas A Delamere, Mohammad Shahidullah, Ursula S. Sandau, Sergio R. OjedaAbstract:Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxydl may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxydl can rescue these RTT deficits, we studied the male progeny of Fxydl null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxydl allele, suggesting that NKA activity is under Fxydl inhibitory control. Deletion of one Fxydl allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxydl failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxydl in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth. (C) 2018 Elsevier B.V. All rights reserved.
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correcting deregulated fxyd1 expression ameliorates a behavioral impairment in a mouse model of rett syndrome
Brain Research, 2013Co-Authors: Valerie Matagne, Sarojini S Budden, Jacob Raber, Sergio R. OjedaAbstract:Abstract Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2. Several genes have been shown to be MECP2 targets. We previously identified FXYD1 (encoding phospholemman; a protein containing the motif phenylalanine-X-tyrosine-aspartate), a gene encoding a transmembrane modulator of the Na, K-ATPase (NKA) enzyme, as one of them. In the absence of MECP2, FXYD1 expression is increased in the frontal cortex (FC) of both RTT patients and Mecp2Bird null mice. Here, we show that Fxyd1 mRNA levels are also increased in the FC and hippocampus (HC) of male mice carrying a truncating mutation of the Mecp2 gene (Mecp2308). To test the hypothesis that some of the behavioral phenotypes seen in these Mecp2 mutants could be ameliorated by genetically preventing the Fxyd1 response to MECP2 deficiency, we crossed Fxyd1 null male mice with Mecp2308 heterozygous females and behaviorally tested the adult male offspring. Mecp2308 mice had impaired HC-dependent novel location recognition, and this impairment was rescued by deletion of both Fxyd1 alleles. No other behavioral or sensorimotor impairments were rescued. These results indicate that reducing FXYD1 levels improves a specific cognitive impairment in MECP2-deficient mice.
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brain region specific expression of fxyd1 an mecp2 target gene is regulated by epigenetic mechanisms
Journal of Neuroscience Research, 2011Co-Authors: Fatima Banine, Valerie Matagne, Larry S Sherman, Sergio R. OjedaAbstract:Fxyd1 encodes a trans-membrane protein that modulates Na+,K+-ATPase activity and is a substrate for multiple protein kinases. Fxyd1 expression is repressed by methyl CpG-binding protein 2 (Mecp2) in the frontal cortex (FC) but not in the cerebellum (CB) of the mouse brain. Consistently with these observations, FXYD1 mRNA abundance is increased in the FC of Rett syndrome (RTT) patients with MECP2 mutations. Because Fxyd1 is implicated in the regulation of neuronal excitability, understanding how Fxyd1 expression is controlled is important. Here we report that basal expression of Fxyd1a and Fxyd1b, the two main alternatively spliced forms of Fxyd1 mRNA, is lower in the FC than in the CB. This difference is accompanied by increased Mecp2 recruitment to the promoter region of these two Fxyd1 mRNA forms. DNA methylation of both promoters is more frequent in the FC than in the CB, and in both cases the most frequently methylated CpG dinucleotides are adjacent to [A/T]4 sequences required for high-affinity Mecp2 binding. Consistently with these features of epigenetic silencing, histone 3 acetylated at lysines 9 and 14 (H3K9/14ac) and histone 3 methylated at lysine 4 (H3K4me3), both activating histone marks, were associated with the Fxyd1 promoter to a lesser degree in the FC than in the CB. These results indicate that differential Fxyd1 expression in these two brain regions is, at least in part, regulated by an epigenetic mechanism involving increased DNA methylation of the two alternative Fxyd1 promoters, enhanced Mecp2 recruitment, and reduced association of activating histones. © 2011 Wiley-Liss, Inc.
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fxyd1 a modulator of na k atpase activity facilitates female sexual development by maintaining gonadotrophin releasing hormone neuronal excitability
Journal of Neuroendocrinology, 2009Co-Authors: Cecilia Garciarudaz, Valerie Matagne, Vivianne Deng, Oline K. Rønnekleiv, Martha A Bosch, Alan K Percy, Sergio R. OjedaAbstract:: The excitatory tone to gonadotrophin-releasing hormone (GnRH) neurones is a critical component underlying the pubertal increase in GnRH secretion. However, the homeostatic mechanisms modulating the response of GnRH neurones to excitatory inputs remain poorly understood. A basic mechanism of neuronal homeostasis is the Na(+),K(+)-ATPase-dependent restoration of Na(+) and K(+) transmembrane gradients after neuronal excitation. This activity is reduced in a mouse model of Rett syndrome (RTT), a neurodevelopmental disorder in which expression of FXYD1, a modulator of Na(+),K(+)-ATPase activity, is increased. We now report that the initiation, but not the completion of puberty, is advanced in girls with RTT, and that, in rodents, FXYD1 may contribute to the neuroendocrine regulation of female puberty by modulating GnRH neuronal excitability. Fxyd1 mRNA abundance reaches maximal levels in the female rat hypothalamus by the fourth postnatal week of life (i.e., around the time when the mode of GnRH secretion acquires an adult pattern of release). Although Fxyd1 mRNA expression is low in the hypothalamus, approximately 50% of GnRH neurones contain Fxyd1 transcripts. Whole-cell patch recording of GnRH-EGFP neurones revealed that the neurones of Fxyd1-null female mice respond to somatic current injections with a lower number of action potentials than wild-type cells. Both the age at vaginal opening and at first oestrous were delayed in Fxyd1(-/-) mice, but adult reproductive capacity was normal. These results suggest that FXYD1 contributes to facilitating the advent of puberty by maintaining GnRH neuronal excitability to incoming transsynaptic stimulatory inputs.
Tsung-han Lee - One of the best experts on this subject based on the ideXlab platform.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes.
PLOS ONE, 2018Co-Authors: Wenkai Yang, Chaokai Kang, An Di Hsu, Ivan Pochou Lai, Pei Shao Liao, Tsung-han LeeAbstract:FXYD proteins are the regulators of sodium-potassium ATPase (Na+/K+-ATPase, NKA). In teleosts, NKA is a primary driving force for the operation of many ion transport systems in the osmoregulatory organs (e.g. intestines). Hence, the purpose of this study was to determine the expression of FXYD proteins and NKA α-subunit in the intestines of two closely related medakas (Oryzias dancena and O. latipes), which came from different salinity habitats and have diverse osmoregulatory capabilities, to illustrate the association between NKA and FXYD proteins of two medaka species in response to salinity changes. The results showed that the fxyd12 mRNA was the most predominant in the intestines of both medakas. The association of FXYD12 and NKA in the intestines of the two medaka species was demonstrated via double immunofluorescent staining and co-immunoprecipitation. Upon salinity challenge, the localization of FXYD12 and NKA was similar in the intestines of the two medaka species. However, the expression profiles of intestinal FXYD12 and NKA (mRNA and protein levels), as well as NKA activity differed between the medakas. These results showed that FXYD12 may play a role in modulating NKA activity in the intestines of the two medakas following salinity changes in the maintenance of internal homeostasis. These findings contributed to knowledge of the expression and potential role of vertebrate FXYD12, the regulators of NKA, upon salinity challenge.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes - Fig 1
2018Co-Authors: Wenkai Yang, Chaokai Kang, Ivan Pochou Lai, Pei Shao Liao, An-di Hsu, Tsung-han LeeAbstract:Levels of intestinal fxyd mRNA in the Indian medaka (Od; A) and the Japanese medaka (Ol; B). The values are means ± SEM (total N = 12; N = 4 in the freshwater, brackish water, and seawater group, respectively). Different letters indicate significant differences among fxyd genes, excluding fxyd12 (P < 0.05). A.u., arbitrary units.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes - Fig 5
2018Co-Authors: Wenkai Yang, Chaokai Kang, Ivan Pochou Lai, Pei Shao Liao, An-di Hsu, Tsung-han LeeAbstract:Confocal 3D micrographs of double immunofluorescence staining of NKA α-subunit (NKA; green; A, D) and FXYD12 (red; B, E) in the cryosection of the brackish water-acclimated Indian medaka intestines. Immunosignals of NKA and FXYD12 were both detected in epithelial cell of intestinal villi. The results were similar between the cross section (A-C) and longitudinal section (D-F) of the epithelial cells. The merged image (yellow; C, F) revealed that FXYD12 colocalised to the basolateral membrane of NKA-immunoreactive cells. *, lumen. Scale bar: 10 μm.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes - Fig 4
2018Co-Authors: Wenkai Yang, Chaokai Kang, Ivan Pochou Lai, Pei Shao Liao, An-di Hsu, Tsung-han LeeAbstract:Double immunofluorescence staining of NKA α-subunit (NKA; green; A-C) and FXYD12 (red; D-F) in intestinal cross-cryosections of the Japanese medaka (Ol). The merged images (yellow; G, H, I) revealed that FXYD12 colocalised to the basolateral membrane of NKA-immunoreactive cells in the fresh water- (FW; A, D, G), brackish water- (BW; B, E, H), and seawater- (SW; C, F, I) acclimated fish. V, villus; *, lumen. Scale bar: 20 μm.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes - Fig 3
2018Co-Authors: Wenkai Yang, Chaokai Kang, Ivan Pochou Lai, Pei Shao Liao, An-di Hsu, Tsung-han LeeAbstract:Double immunofluorescence staining of NKA α-subunit (NKA; green; A-C) and FXYD12 (red; D-F) in intestinal cross-cryosections of the Indian medaka (Od). The merged images (yellow; G, H, I) revealed that FXYD12 colocalised in the basolateral membrane of NKA-immunoreactive cells in the fresh water- (FW; A, D, G), brackish water- (BW; B, E, H), and seawater- (SW; C, F, I) acclimated fish. V, villus; *, lumen. Scale bar: 20 μm.
Sarojini S Budden - One of the best experts on this subject based on the ideXlab platform.
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correcting deregulated fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in mecp2 deficient male mice
Brain Research, 2018Co-Authors: Valerie Matagne, Matthew Frerking, Sarojini S Budden, Joyce Wondolowski, Nicholas A Delamere, Mohammad Shahidullah, Ursula S. Sandau, Sergio R. OjedaAbstract:Abstract Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxyd1 can rescue these RTT deficits, we studied the male progeny of Fxyd1 null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxyd1 allele, suggesting that NKA activity is under Fxyd1 inhibitory control. Deletion of one Fxyd1 allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxyd1 failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxyd1 in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth.
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Correcting deregulated Fxydl expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice
Brain Research, 2018Co-Authors: Valerie Matagne, Matthew Frerking, Sarojini S Budden, Joyce Wondolowski, Nicholas A Delamere, Mohammad Shahidullah, Ursula S. Sandau, Sergio R. OjedaAbstract:Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na+, K+-ATPase activity (NKA), an excess of Fxydl may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxydl can rescue these RTT deficits, we studied the male progeny of Fxydl null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxydl allele, suggesting that NKA activity is under Fxydl inhibitory control. Deletion of one Fxydl allele also prevented the increased extracellular potassium (K+) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxydl failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxydl in the absence of MeCP2 results in deregulation of endogenous K+ conductances functionally associated with NKA and leads to stunted neuronal growth. (C) 2018 Elsevier B.V. All rights reserved.
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correcting deregulated fxyd1 expression ameliorates a behavioral impairment in a mouse model of rett syndrome
Brain Research, 2013Co-Authors: Valerie Matagne, Sarojini S Budden, Jacob Raber, Sergio R. OjedaAbstract:Abstract Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2. Several genes have been shown to be MECP2 targets. We previously identified FXYD1 (encoding phospholemman; a protein containing the motif phenylalanine-X-tyrosine-aspartate), a gene encoding a transmembrane modulator of the Na, K-ATPase (NKA) enzyme, as one of them. In the absence of MECP2, FXYD1 expression is increased in the frontal cortex (FC) of both RTT patients and Mecp2Bird null mice. Here, we show that Fxyd1 mRNA levels are also increased in the FC and hippocampus (HC) of male mice carrying a truncating mutation of the Mecp2 gene (Mecp2308). To test the hypothesis that some of the behavioral phenotypes seen in these Mecp2 mutants could be ameliorated by genetically preventing the Fxyd1 response to MECP2 deficiency, we crossed Fxyd1 null male mice with Mecp2308 heterozygous females and behaviorally tested the adult male offspring. Mecp2308 mice had impaired HC-dependent novel location recognition, and this impairment was rescued by deletion of both Fxyd1 alleles. No other behavioral or sensorimotor impairments were rescued. These results indicate that reducing FXYD1 levels improves a specific cognitive impairment in MECP2-deficient mice.
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fxyd1 is an mecp2 target gene overexpressed in the brains of rett syndrome patients and mecp2 null mice
Human Molecular Genetics, 2007Co-Authors: Vivianne Deng, Fatima Banine, Valerie Matagne, Matthew Frerking, Patricia Ohliger, Sarojini S Budden, Gregory A. Dissen, Jonathan Pevsner, Larry S ShermanAbstract:Rett syndrome (RTT) is an X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. Direct MeCP2 targets underlying RTT pathogenesis remain largely unknown. Here, we report that FXYD1, which encodes a transmembrane modulator of Na + ,K + -ATPase activity, is elevated in frontal cortex (FC) neurons of RTT patients and Mecp2-null mice. Increasing neuronal FXDY1 expression is sufficient to reduce dendritic arborization and spine formation, hallmarks of RTT neuropathology. Mecp2-null mouse cortical neurons have diminished Na + ,K + -ATPase activity, suggesting that aberrant FXYD1 expression contributes to abnormal neuronal activity in RTT. MeCP2 represses Fxyd1 transcription through direct interactions with sequences in the Fxyd1 promoter that are methylated in FC neurons. FXYD1 is therefore a MeCP2 target gene whose de-repression may directly contribute to RTT neuronal pathogenesis.
Wenkai Yang - One of the best experts on this subject based on the ideXlab platform.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes.
PLOS ONE, 2018Co-Authors: Wenkai Yang, Chaokai Kang, An Di Hsu, Ivan Pochou Lai, Pei Shao Liao, Tsung-han LeeAbstract:FXYD proteins are the regulators of sodium-potassium ATPase (Na+/K+-ATPase, NKA). In teleosts, NKA is a primary driving force for the operation of many ion transport systems in the osmoregulatory organs (e.g. intestines). Hence, the purpose of this study was to determine the expression of FXYD proteins and NKA α-subunit in the intestines of two closely related medakas (Oryzias dancena and O. latipes), which came from different salinity habitats and have diverse osmoregulatory capabilities, to illustrate the association between NKA and FXYD proteins of two medaka species in response to salinity changes. The results showed that the fxyd12 mRNA was the most predominant in the intestines of both medakas. The association of FXYD12 and NKA in the intestines of the two medaka species was demonstrated via double immunofluorescent staining and co-immunoprecipitation. Upon salinity challenge, the localization of FXYD12 and NKA was similar in the intestines of the two medaka species. However, the expression profiles of intestinal FXYD12 and NKA (mRNA and protein levels), as well as NKA activity differed between the medakas. These results showed that FXYD12 may play a role in modulating NKA activity in the intestines of the two medakas following salinity changes in the maintenance of internal homeostasis. These findings contributed to knowledge of the expression and potential role of vertebrate FXYD12, the regulators of NKA, upon salinity challenge.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes - Fig 1
2018Co-Authors: Wenkai Yang, Chaokai Kang, Ivan Pochou Lai, Pei Shao Liao, An-di Hsu, Tsung-han LeeAbstract:Levels of intestinal fxyd mRNA in the Indian medaka (Od; A) and the Japanese medaka (Ol; B). The values are means ± SEM (total N = 12; N = 4 in the freshwater, brackish water, and seawater group, respectively). Different letters indicate significant differences among fxyd genes, excluding fxyd12 (P < 0.05). A.u., arbitrary units.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes - Fig 5
2018Co-Authors: Wenkai Yang, Chaokai Kang, Ivan Pochou Lai, Pei Shao Liao, An-di Hsu, Tsung-han LeeAbstract:Confocal 3D micrographs of double immunofluorescence staining of NKA α-subunit (NKA; green; A, D) and FXYD12 (red; B, E) in the cryosection of the brackish water-acclimated Indian medaka intestines. Immunosignals of NKA and FXYD12 were both detected in epithelial cell of intestinal villi. The results were similar between the cross section (A-C) and longitudinal section (D-F) of the epithelial cells. The merged image (yellow; C, F) revealed that FXYD12 colocalised to the basolateral membrane of NKA-immunoreactive cells. *, lumen. Scale bar: 10 μm.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes - Fig 4
2018Co-Authors: Wenkai Yang, Chaokai Kang, Ivan Pochou Lai, Pei Shao Liao, An-di Hsu, Tsung-han LeeAbstract:Double immunofluorescence staining of NKA α-subunit (NKA; green; A-C) and FXYD12 (red; D-F) in intestinal cross-cryosections of the Japanese medaka (Ol). The merged images (yellow; G, H, I) revealed that FXYD12 colocalised to the basolateral membrane of NKA-immunoreactive cells in the fresh water- (FW; A, D, G), brackish water- (BW; B, E, H), and seawater- (SW; C, F, I) acclimated fish. V, villus; *, lumen. Scale bar: 20 μm.
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Intestinal FXYD12 and sodium-potassium ATPase: A comparative study on two euryhaline medakas in response to salinity changes - Fig 3
2018Co-Authors: Wenkai Yang, Chaokai Kang, Ivan Pochou Lai, Pei Shao Liao, An-di Hsu, Tsung-han LeeAbstract:Double immunofluorescence staining of NKA α-subunit (NKA; green; A-C) and FXYD12 (red; D-F) in intestinal cross-cryosections of the Indian medaka (Od). The merged images (yellow; G, H, I) revealed that FXYD12 colocalised in the basolateral membrane of NKA-immunoreactive cells in the fresh water- (FW; A, D, G), brackish water- (BW; B, E, H), and seawater- (SW; C, F, I) acclimated fish. V, villus; *, lumen. Scale bar: 20 μm.
