Dataset Information

The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions.

ABSTRACT: In response to neurodegeneration, the adult mammalian brain activates a cellular cascade that results in reactive astrogliosis and microgliosis. The mechanism through which astrocytes become reactive and the physiological consequences of their activation in response to neurodegeneration is complex. While the activation and proliferation of astrocytes has been shown to occur during massive neuronal cell death, the functional relationship between these two events has not been clearly elucidated. Here we show that in response to kainic acid- (KA) induced neurodegeneration, the mitogen sonic hedgehog (SHH) is upregulated in reactive astrocytes. SHH activity peaks at 7 days and is accompanied by increased Gli activity and elevated proliferation in several cell types. To determine the functional role of SHH-Gli signaling following KA lesions, we used a pharmacological approach to show that SHH secreted by astrocytes drives the activation and proliferation of astrocytes and microglia. The consequences of SHH-Gli signaling in KA-induced lesions appear to be independent of the severity of neurodegeneration.

SUBMITTER: Pitter KL

PROVIDER: S-EPMC4489138 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions.

Pitter Kenneth L KL Tamagno Ilaria I Feng Xi X Ghosal Kaushik K Amankulor Nduka N Holland Eric C EC Hambardzumyan Dolores D

Glia 20140604 10

In response to neurodegeneration, the adult mammalian brain activates a cellular cascade that results in reactive astrogliosis and microgliosis. The mechanism through which astrocytes become reactive and the physiological consequences of their activation in response to neurodegeneration is complex. While the activation and proliferation of astrocytes has been shown to occur during massive neuronal cell death, the functional relationship between these two events has not been clearly elucidated. H ...[more]

PMID: 24895267

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Project description:The increasing number of developmental events and molecular mechanisms associated with the Hedgehog (Hh) pathway from Drosophila to vertebrates, suggest that gene regulation is crucial for diverse cellular responses, including target genes not yet described. Although several high-throughput, genome-wide approaches have yielded information at the genomic, transcriptional and proteomic levels, the specificity of Gli binding sites related to direct target gene activation still remain elusive. This study aims to identify novel putative targets of Gli transcription factors through a protein-DNA binding assay using yeast, and validating a subset of targets both in-vitro and in-vivo. Testing in different Hh/Gli gain- and loss-of-function scenarios we here identified known (e.g., ptc1) and novel Hh-regulated genes in zebrafish embryos.The combined yeast-based screening and MEME/MAST analysis were able to predict Gli transcription factor binding sites, and position mapping of these sequences upstream or in the first intron of promoters served to identify new putative target genes of Gli regulation. These candidates were validated by qPCR in combination with either the pharmacological Hh/Gli antagonist cyc or the agonist pur in Hh-responsive C3H10T1/2 cells. We also used small-hairpin RNAs against Gli proteins to evaluate targets and confirm specific Gli regulation their expression. Taking advantage of mutants that have been identified affecting different components of the Hh/Gli signaling system in the zebrafish model, we further analyzed specific novel candidates. Studying Hh function with pharmacological inhibition or activation complemented these genetic loss-of-function approaches. We provide evidence that in zebrafish embryos, Hh signaling regulates sfrp2, neo1, and c-myc expression in-vivo.A recently described yeast-based screening allowed us to identify new Hh/Gli target genes, functionally important in different contexts of vertebrate embryonic development.

Dataset Information

The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions.

Publications

The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions.

Similar Datasets

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