MeCP2 Deficiency Leads to Loss of Glial Kir4.1

ENeuro
Uri KahanovitchMichelle Olsen

Abstract

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder usually caused by mutations in methyl-CpG-binding protein 2 (MeCP2). RTT is typified by apparently normal development until 6-18 mo of age, when motor and communicative skills regress and hand stereotypies, autonomic symptoms, and seizures present. Restoration of MeCP2 function selectively to astrocytes reversed several deficits in a murine model of RTT, but the mechanism of this rescue is unknown. Astrocytes carry out many essential functions required for normal brain functioning, including extracellular K+ buffering. Kir4.1, an inwardly rectifying K+ channel, is largely responsible for the channel-mediated K+ regulation by astrocytes. Loss-of-function mutations in Kir4.1 in human patients result in a severe neurodevelopmental disorder termed EAST or SESAME syndrome. Here, we evaluated astrocytic Kir4.1 expression in a murine model of Rett syndrome. We demonstrate by chromatin immunoprecipitation analysis that Kir4.1 is a direct molecular target of MeCP2. Astrocytes from Mecp2-deficient mice express significantly less Kir4.1 mRNA and protein, which translates into a >50% deficiency in Ba2+-sensitive Kir4.1-mediated currents, and impaired extracellular potassium dyn...Continue Reading

Citations

Jun 20, 2019·Current Protocols in Neuroscience·Leanne M HoltMichelle L Olsen
Aug 8, 2019·International Journal of Molecular Sciences·Uri KahanovitchMichelle L Olsen
Oct 18, 2019·International Journal of Molecular Sciences·Shilpa D KadamConstance Smith-Hicks
Jul 14, 2019·Trends in Neurosciences·Noémie CrestoNathalie Rouach
May 20, 2021·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Peipei ChengYasong Du
Feb 28, 2021·Journal of Neurochemistry·Santosh R D'Mello

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Methods Mentioned

BETA
PCR
protein assay
ChIP
immunoprecipitation

Software Mentioned

ImageJ
MYSTAT
Systat
Excel
Clampex
GraphPad
InStat
Origin

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