Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice

Valerie Matagne, Joyce Wondolowski, Matthew Frerking, Mohammad Shahidullah, Nicholas A. Delamere, Ursula S. Sandau, Sarojini Budden, Sergio Ojeda

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)45-52
Number of pages8
JournalBrain Research
Volume1697
DOIs
StatePublished - Oct 15 2018

Fingerprint

Neuronal Plasticity
Potassium
Homeostasis
Rett Syndrome
Frontal Lobe
Alleles
Growth Disorders
Neurons
Wild Animals
Ouabain
Genes
Membrane Proteins
sodium-translocating ATPase
Phenotype
Mutation

Keywords

  • Mecp2 deficiency
  • Neuronal morphology
  • Potassium efflux
  • Rett syndrome
  • Sodium-potassium ATPase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Cite this

Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice. / Matagne, Valerie; Wondolowski, Joyce; Frerking, Matthew; Shahidullah, Mohammad; Delamere, Nicholas A.; Sandau, Ursula S.; Budden, Sarojini; Ojeda, Sergio.

In: Brain Research, Vol. 1697, 15.10.2018, p. 45-52.

Research output: Contribution to journalArticle

Matagne, Valerie ; Wondolowski, Joyce ; Frerking, Matthew ; Shahidullah, Mohammad ; Delamere, Nicholas A. ; Sandau, Ursula S. ; Budden, Sarojini ; Ojeda, Sergio. / Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice. In: Brain Research. 2018 ; Vol. 1697. pp. 45-52.
@article{762ba18d644b490a8231a05fa61a026f,
title = "Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice",
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.",
keywords = "Mecp2 deficiency, Neuronal morphology, Potassium efflux, Rett syndrome, Sodium-potassium ATPase",
author = "Valerie Matagne and Joyce Wondolowski and Matthew Frerking and Mohammad Shahidullah and Delamere, {Nicholas A.} and Sandau, {Ursula S.} and Sarojini Budden and Sergio Ojeda",
year = "2018",
month = "10",
day = "15",
doi = "10.1016/j.brainres.2018.06.013",
language = "English (US)",
volume = "1697",
pages = "45--52",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",

}

TY - JOUR

T1 - Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice

AU - Matagne, Valerie

AU - Wondolowski, Joyce

AU - Frerking, Matthew

AU - Shahidullah, Mohammad

AU - Delamere, Nicholas A.

AU - Sandau, Ursula S.

AU - Budden, Sarojini

AU - Ojeda, Sergio

PY - 2018/10/15

Y1 - 2018/10/15

N2 - 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.

AB - 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.

KW - Mecp2 deficiency

KW - Neuronal morphology

KW - Potassium efflux

KW - Rett syndrome

KW - Sodium-potassium ATPase

UR - http://www.scopus.com/inward/record.url?scp=85048564809&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048564809&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2018.06.013

DO - 10.1016/j.brainres.2018.06.013

M3 - Article

C2 - 29902467

AN - SCOPUS:85048564809

VL - 1697

SP - 45

EP - 52

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -