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WNT protein-independent constitutive nuclear localization of beta-catenin protein and its low degradation rate in thalamic neurons.

ABSTRACT: Nuclear localization of ?-catenin is a hallmark of canonical Wnt signaling, a pathway that plays a crucial role in brain development and the neurogenesis of the adult brain. We recently showed that ?-catenin accumulates specifically in mature thalamic neurons, where it regulates the expression of the Ca(v)3.1 voltage-gated calcium channel gene. Here, we investigated the mechanisms underlying ?-catenin accumulation in thalamic neurons. We report that a lack of soluble factors produced either by glia or cortical neurons does not impair nuclear ?-catenin accumulation in thalamic neurons. We next found that the number of thalamic neurons with ?-catenin nuclear localization did not change when the Wnt/Dishevelled signaling pathway was inhibited by Dickkopf1 or a dominant negative mutant of Dishevelled3. These results suggest a WNT-independent cell-autonomous mechanism. We found that the protein levels of APC, AXIN1, and GSK3?, components of the ?-catenin degradation complex, were lower in the thalamus than in the cortex of the adult rat brain. Reduced levels of these proteins were also observed in cultured thalamic neurons compared with cortical cultures. Finally, pulse-chase experiments confirmed that cytoplasmic ?-catenin turnover was slower in thalamic neurons than in cortical neurons. Altogether, our data indicate that the nuclear localization of ?-catenin in thalamic neurons is their cell-intrinsic feature, which was WNT-independent but associated with low levels of proteins involved in ?-catenin labeling for ubiquitination and subsequent degradation.

SUBMITTER: Misztal K

PROVIDER: S-EPMC3173118 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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WNT protein-independent constitutive nuclear localization of beta-catenin protein and its low degradation rate in thalamic neurons.

Misztal Katarzyna K Wisniewska Marta B MB Ambrozkiewicz Mateusz M Nagalski Andrzej A Kuznicki Jacek J

The Journal of biological chemistry 20110709 36

Nuclear localization of β-catenin is a hallmark of canonical Wnt signaling, a pathway that plays a crucial role in brain development and the neurogenesis of the adult brain. We recently showed that β-catenin accumulates specifically in mature thalamic neurons, where it regulates the expression of the Ca(v)3.1 voltage-gated calcium channel gene. Here, we investigated the mechanisms underlying β-catenin accumulation in thalamic neurons. We report that a lack of soluble factors produced either by g ...[more]

PMID: 21757747

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Project description:BACKGROUND: LEF1/TCF transcription factors and their activator ?-catenin are effectors of the canonical Wnt pathway. Although Wnt/?-catenin signaling has been implicated in neurodegenerative and psychiatric disorders, its possible role in the adult brain remains enigmatic. To address this issue, we sought to identify the genetic program activated by ?-catenin in neurons. We recently showed that ?-catenin accumulates specifically in thalamic neurons where it activates Cacna1g gene expression. In the present study, we combined bioinformatics and experimental approaches to find new ?-catenin targets in the adult thalamus. RESULTS: We first selected the genes with at least two conserved LEF/TCF motifs within the regulatory elements. The resulting list of 428 putative LEF1/TCF targets was significantly enriched in known Wnt targets, validating our approach. Functional annotation of the presumed targets also revealed a group of 41 genes, heretofore not associated with Wnt pathway activity, that encode proteins involved in neuronal signal transmission. Using custom polymerase chain reaction arrays, we profiled the expression of these genes in the rat forebrain. We found that nine of the analyzed genes were highly expressed in the thalamus compared with the cortex and hippocampus. Removal of nuclear ?-catenin from thalamic neurons in vitro by introducing its negative regulator Axin2 reduced the expression of six of the nine genes. Immunoprecipitation of chromatin from the brain tissues confirmed the interaction between ?-catenin and some of the predicted LEF1/TCF motifs. The results of these experiments validated four genes as authentic and direct targets of ?-catenin: Gabra3 for the receptor of GABA neurotransmitter, Calb2 for the Ca(2+)-binding protein calretinin, and the Cacna1g and Kcna6 genes for voltage-gated ion channels. Two other genes from the latter cluster, Cacna2d2 and Kcnh8, appeared to be regulated by ?-catenin, although the binding of ?-catenin to the regulatory sequences of these genes could not be confirmed. CONCLUSIONS: In the thalamus, ?-catenin regulates the expression of a novel group of genes that encode proteins involved in neuronal excitation. This implies that the transcriptional activity of ?-catenin is necessary for the proper excitability of thalamic neurons, may influence activity in the thalamocortical circuit, and may contribute to thalamic pathologies.

Dataset Information

WNT protein-independent constitutive nuclear localization of beta-catenin protein and its low degradation rate in thalamic neurons.

Publications

WNT protein-independent constitutive nuclear localization of beta-catenin protein and its low degradation rate in thalamic neurons.

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