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Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis.

ABSTRACT: Brain injury may result in the development of epilepsy, one of the most common neurological disorders. We previously demonstrated that albumin is critical in the generation of epilepsy after blood-brain barrier (BBB) compromise. Here, we identify TGF-beta pathway activation as the underlying mechanism. We demonstrate that direct activation of the TGF-beta pathway by TGF-beta1 results in epileptiform activity similar to that after exposure to albumin. Coimmunoprecipitation revealed binding of albumin to TGF-beta receptor II, and Smad2 phosphorylation confirmed downstream activation of this pathway. Transcriptome profiling demonstrated similar expression patterns after BBB breakdown, albumin, and TGF-beta1 exposure, including modulation of genes associated with the TGF-beta pathway, early astrocytic activation, inflammation, and reduced inhibitory transmission. Importantly, TGF-beta pathway blockers suppressed most albumin-induced transcriptional changes and prevented the generation of epileptiform activity. Our present data identifies the TGF-beta pathway as a novel putative epileptogenic signaling cascade and therapeutic target for the prevention of injury-induced epilepsy.

SUBMITTER: Cacheaux LP

PROVIDER: S-EPMC2875073 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis.

Cacheaux Luisa P LP Ivens Sebastian S David Yaron Y Lakhter Alexander J AJ Bar-Klein Guy G Shapira Michael M Heinemann Uwe U Friedman Alon A Kaufer Daniela D

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090701 28

Brain injury may result in the development of epilepsy, one of the most common neurological disorders. We previously demonstrated that albumin is critical in the generation of epilepsy after blood-brain barrier (BBB) compromise. Here, we identify TGF-beta pathway activation as the underlying mechanism. We demonstrate that direct activation of the TGF-beta pathway by TGF-beta1 results in epileptiform activity similar to that after exposure to albumin. Coimmunoprecipitation revealed binding of alb ...[more]

PMID: 19605630

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Project description:Epithelial-mesenchymal transition (EMT) describes a process whereby polarized epithelial cells with restricted migration transform into elongated spindle-shaped mesenchymal cells with enhanced motility and invasiveness. Although there are some molecular markers for this process, including the down-regulation of E-cadherin, our understanding of plasma membrane (PM) and associated proteins involved in EMT is limited. To specifically explore molecular alterations occurring at the PM, we used the cationic colloidal silica isolation technique to purify PM fractions from epithelial Madin-Darby canine kidney cells during Ras/TGF-β-mediated EMT. Proteins in the isolated membrane fractions were separated by one-dimensional SDS-PAGE and subjected to nano-LC-MS/MS-based protein identification. In this study, the first membrane protein analysis of an EMT model, we identified 805 proteins and determined their differential expression using label-free spectral counting. These data reveal that Madin-Darby canine kidney cells switch from cadherin-mediated to integrin-mediated adhesion following Ras/TGF-β-mediated EMT. Thus, during the EMT process, E-cadherin, claudin 4, desmoplakin, desmoglein-2, and junctional adhesion molecule A were down-regulated, whereas integrins α6β1, α3β1, α2β1, α5β1, αVβ1, and αVβ3 along with their extracellular ligands collagens I and V and fibronectin had increased expression levels. Conspicuously, Wnt-5a expression was elevated in cells undergoing EMT, and transient Wnt-5a siRNA silencing attenuated both cell migration and invasion in these cells. Furthermore, Wnt-5a expression suppressed canonical Wnt signaling induced by Wnt-3a. Wnt-5a may act through the planar cell polarity pathway of the non-canonical Wnt signaling pathway as several of the components and modulators (Wnt-5a, -5b, frizzled 6, collagen triple helix repeat-containing protein 1, tyrosine-protein kinase 7, RhoA, Rac, and JNK) were found to be up-regulated during Ras/TGF-β-mediated EMT.

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Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis.

Publications

Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis.

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