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Novel ?-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability.

ABSTRACT: 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.

SUBMITTER: Wisniewska MB

PROVIDER: S-EPMC3532193 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability.

Wisniewska Marta B MB Nagalski Andrzej A Dabrowski Michal M Misztal Katarzyna K Kuznicki Jacek J

BMC genomics 20121117

<h4>Background</h4>LEF1/TCF transcription factors and their activator β-catenin are effectors of the canonical Wnt pathway. Although Wnt/β-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 β-catenin in neurons. We recently showed that β-catenin accumulates specifically in thalamic neurons where it activates Cacna1g gene expressi ...[more]

PMID: 23157480

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Project description:Thalamic neurons have been long assumed to fire in tonic mode during perceptive states, and in burst mode during sleep and unconsciousness. However, recent evidence suggests that bursts may also be relevant in the encoding of sensory information. Here, we explore the neural code of such thalamic bursts. In order to assess whether the burst code is generic or whether it depends on the detailed properties of each bursting neuron, we analyzed two neuron models incorporating different levels of biological detail. One of the models contained no information of the biophysical processes entailed in spike generation, and described neuron activity at a phenomenological level. The second model represented the evolution of the individual ionic conductances involved in spiking and bursting, and required a large number of parameters. We analyzed the models' input selectivity using reverse correlation methods and information theory. We found that n-spike bursts from both models transmit information by modulating their spike count in response to changes to instantaneous input features, such as slope, phase, amplitude, etc. The stimulus feature that is most efficiently encoded by bursts, however, need not coincide with one of such classical features. We therefore searched for the optimal feature among all those that could be expressed as a linear transformation of the time-dependent input current. We found that bursting neurons transmitted 6 times more information about such more general features. The relevant events in the stimulus were located in a time window spanning ~100 ms before and ~20 ms after burst onset. Most importantly, the neural code employed by the simple and the biologically realistic models was largely the same, implying that the simple thalamic neuron model contains the essential ingredients that account for the computational properties of the thalamic burst code. Thus, our results suggest the n-spike burst code is a general property of thalamic neurons.

Project description:Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.

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Novel ?-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability.

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Novel β-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability.

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