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Regulation of GFAP Expression.

ABSTRACT: Expression of the GFAP gene has attracted considerable attention because its onset is a marker for astrocyte development, its upregulation is a marker for reactive gliosis, and its predominance in astrocytes provides a tool for their genetic manipulation. The literature on GFAP regulation is voluminous, as almost any perturbation of development or homeostasis in the CNS will lead to changes in its expression. In this review, we limit our discussion to mechanisms proposed to regulate GFAP synthesis through a direct interaction with its gene or mRNA. Strengths and weaknesses of the supportive experimental findings are described, and suggestions made for additional studies. This review covers 15 transcription factors, DNA and histone methylation, and microRNAs. The complexity involved in regulating the expression of this intermediate filament protein suggests that GFAP function may vary among both astrocyte subtypes and other GFAP-expressing cells, as well as during development and in response to perturbations.

SUBMITTER: Brenner M

PROVIDER: S-EPMC7897836 | biostudies-literature | 2021 Jan-Dec

REPOSITORIES: biostudies-literature

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Regulation of GFAP Expression.

Brenner Michael M Messing Albee A

ASN neuro 20210101

Expression of the GFAP gene has attracted considerable attention because its onset is a marker for astrocyte development, its upregulation is a marker for reactive gliosis, and its predominance in astrocytes provides a tool for their genetic manipulation. The literature on GFAP regulation is voluminous, as almost any perturbation of development or homeostasis in the CNS will lead to changes in its expression. In this review, we limit our discussion to mechanisms proposed to regulate GFAP synthes ...[more]

PMID: 33601918

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Project description:Recently, we have identified two astrocytic subpopulations in the cortex of GFAP-EGFP mice, in which the astrocytes are visualized by the enhanced green-fluorescent protein (EGFP) under the control of the human glial fibrillary acidic protein (GFAP) promotor. These astrocytic subpopulations, termed high response- (HR-) and low response- (LR-) astrocytes, differed in the extent of their swelling during oxygen-glucose deprivation (OGD). In the present study we focused on identifying the ion channels or transporters that might underlie the different capabilities of these two astrocytic subpopulations to regulate their volume during OGD. Using three-dimensional confocal morphometry, which enables quantification of the total astrocytic volume, the effects of selected inhibitors of K? and Cl? channels/transporters or glutamate transporters on astrocyte volume changes were determined during 20 minute-OGD in situ. The inhibition of volume regulated anion channels (VRACs) and two-pore domain potassium channels (K(2P)) highlighted their distinct contributions to volume regulation in HR-/LR-astrocytes. While the inhibition of VRACs or K(2P) channels revealed their contribution to the swelling of HR-astrocytes, in LR-astrocytes they were both involved in anion/K? effluxes. Additionally, the inhibition of Na?-K?-Cl? co-transporters in HR-astrocytes led to a reduction of cell swelling, but it had no effect on LR-astrocyte volume. Moreover, employing real-time single-cell quantitative polymerase chain reaction (PCR), we characterized the expression profiles of EGFP-positive astrocytes with a focus on those ion channels and transporters participating in astrocyte swelling and volume regulation. The PCR data revealed the existence of two astrocytic subpopulations markedly differing in their gene expression levels for inwardly rectifying K? channels (Kir4.1), K(2P) channels (TREK-1 and TWIK-1) and Cl? channels (ClC2). Thus, we propose that the diverse volume changes displayed by cortical astrocytes during OGD mainly result from their distinct expression patterns of ClC2 and K(2P) channels.

Project description:Alexander's disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a "threshold hypothesis" has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization.

Dataset Information

Regulation of GFAP Expression.

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Regulation of GFAP Expression.

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