Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength

Kelley, Kevin W.; Haim, Lucile Ben; Schirmer, Lucas; Tyzack, Giulia E.; Tolman, Michaela; Miller, John G.; Tsai, Hui-Hsin; Chang, Sam K. C.; Molofsky, Anna V.; Yang, Yongjie; Patani, Rickie; Lakatos, András; Ullian, Erik M.; Rowitch, David H.

doi:10.1016/j.neuron.2018.03.010

Cited by 113 publications

(138 citation statements)

References 98 publications

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“…To ascertain if DNA hypermethylation may serve as a common mechanism of regulation of the Kcnj10 gene in injury we next evaluated the methylation status of Kcnj10 following trauma in a different CNS region. We and others have shown Kir4.1 expression is highest in caudal brain structures, particularly spinal cord gray matter (Kelley et al, ; Olsen et al, ; Olsen et al, ). During rodent postnatal development, Kcnj10 mRNA expression is higher in spinal cord relative to cortical regions and shows earlier developmental upregulation.…”

Section: Resultsmentioning

confidence: 60%

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Boni

Kahanovitch

Nwaobi

et al. 2020

Glia

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Kir4.1, a glial-specific inwardly rectifying potassium channel, is implicated in astrocytic maintenance of K + homeostasis. Underscoring the role of Kir4.1 in central nervous system (CNS) functioning, genetic mutations in KCNJ10, the gene which encodes Kir4.1, causes seizures, ataxia and developmental disability in humans.Kir4.1 protein and mRNA loss are consistently observed in CNS injury and neurological diseases linked to hyperexcitability and neuronal dysfunction, leading to the notion that Kir4.1 represents an attractive therapeutic target. Despite this, little is understood regarding the mechanisms that underpin this downregulation. Previous work by our lab revealed that DNA hypomethylation of the Kcnj10 gene functions to regulate mRNA levels during astrocyte maturation whereas hypermethylation in vitro led to decreased promoter activity. In the present study, we utilized two vastly different injury models with known acute and chronic loss of Kir4.1 protein and mRNA to evaluate the methylation status of Kcnj10 as a candidate molecular mechanism for reduced transcription and subsequent protein loss. Examining whole hippocampal tissue and isolated astrocytes, in a lithium-pilocarpine model of epilepsy, we consistently identified hypermethylation of CpG island two, which resides in the large intronic region spanning the Kcnj10 gene. Strikingly similar results were observed using the second injury paradigm, a fifth cervical (C5) vertebral hemi-contusion model of spinal cord injury. Our previous work indicates the same gene region is significantly hypomethylated when transcription increases during astrocyte maturation.Our results suggest that DNA methylation can bidirectionally modulate Kcnj10 transcription and may represent a targetable molecular mechanism for the restoring astroglial Kir4.1 expression following CNS insult. K E Y W O R D S astrocyte, DNA methylation, Kcnj10, Kir4.1, Pilocarpine

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Section: Resultsmentioning

confidence: 60%

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Boni

Kahanovitch

Nwaobi

et al. 2020

Glia

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“…verified that Kir4.1 and Cx43 are bona fide substrates of N4-2. These data identify a new level of regulation of the major astrocytic K + channel Kir4.1 that operates posttranslationally, i.e downstream of previously characterized transcriptional regulation (Farmer et al, 2016;Kelley et al, 2018), to control astrocyte function. Disruption of such Kir4.1 regulations could be the bases of several neurological disorders, including amyotrophic lateral sclerosis and depression (Cui et al, 2018).…”

Section: Subsequent Biochemical (Figures 3f-3h) and Qrt-pcr Analysesmentioning

confidence: 70%

Physiological and pathophysiological homeostasis of astroglial channel proteins by Nedd4-2

Altas

Solis

et al. 2019

Preprint

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ORCID for Hiroshi Kawbae; https://orcid.org/0000-0001-5650-8696 CONDENSED TITLE:Ubiquitination of Astrocytic Channels by Nedd4-2 SUMMARY:Ubiquitination is a key regulatory machinery for protein expression. Our present work provides evidence that astrocytic ion channel proteostasis coordinated by an E3 ubiquitin ligase Nedd4-2 is of particular importance for the maintenance of neuronal network activity. ABSTRACTNedd4-2 is an E3 ubiquitin ligase, missense mutation of which is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K + channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of γ-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity, and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy.

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“…In our study, the quantification of astrocyte layer genes uniquely showed peaks and troughs of expression across the superficial-to-deep cortex, as well as differences across functionally distinct cortical areas. As prior studies show that regionrestricted astrocyte mRNA and protein expression are predictors of functions tailored to support of local neural circuits (8,30,31), astrocyte laminar genes indicate potential additional localized functions (32).…”

Section: Discussionmentioning

confidence: 89%

Single-cell in situ transcriptomic map of astrocyte cortical layer diversity

Bayraktar

Bartels

Polioudakis

et al. 2018

Preprint

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During organogenesis, patterns and gradients of gene expression underlie organization and diversified cell specification to generate complex tissue architecture. While the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells are diversified to mimic neuronal laminae or show distinct layering.To determine the molecular architecture of the mammalian cortex, we developed a highcontent pipeline that can quantify single-cell gene expression in situ. The Large-area Spatial Transcriptomic (LaST) map confirmed expected cortical neuron layer organization and also revealed a novel neuronal identity signature. Screening 46 candidate genes for astrocyte diversity across the cortex, we identified grey matter superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from neurons. Astrocyte layers formed in early postnatal cortex and mostly persisted in adult mouse and human cortex. Mutations that shifted neuronal post-mitotic identity or organization were sufficient to alter glial layering, indicating an instructive role for neuronal cues. In normal mouse cortex, astrocyte layer patterns showed area diversity between functionally distinct cortical regions. These findings indicate that excitatory neurons and astrocytes cells are organized into distinct lineage-associated laminae, which give rise to higher order neuroglial complexity of cortical architecture.

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Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength

Cited by 113 publications

References 98 publications

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Physiological and pathophysiological homeostasis of astroglial channel proteins by Nedd4-2

Single-cell in situ transcriptomic map of astrocyte cortical layer diversity

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