LEF1/beta-catenin complex regulates transcription of the Cav3.1 calcium channel gene (Cacna1g) in thalamic neurons of the adult brain.
beta-Catenin, together with LEF1/TCF transcription factors, activates genes involved in the proliferation and differentiation of neuronal precursor cells. In mature neurons, beta-catenin participates in dendritogenesis and synaptic function as a component of the cadherin cell adhesion complex. However, the transcriptional activity of beta-catenin in these cells remains elusive. In the present study, we found that in the adult mouse brain, beta-catenin and LEF1 accumulate in the nuclei of neurons specifically in the thalamus. The particular electrophysiological properties of thalamic neurons depend on T-type calcium channels. Cav3.1 is the predominant T-type channel subunit in the thalamus, and we hypothesized that the Cacna1g gene encoding Cav3.1 is a target of the LEF1/beta-catenin complex. We demonstrated that the expression of Cacna1g is high in the thalamus and is further increased in thalamic neurons treated in vitro with LiCl or WNT3A, activators of beta-catenin. Luciferase reporter assays confirmed that the Cacna1G promoter is activated by LEF1 and beta-catenin, and footprinting analysis revealed four LEF1 binding sites in the proximal region of this promoter. Chromatin immunoprecipitation demonstrated that the Cacna1g proximal promoter is occupied by beta-catenin in vivo in the thalamus, but not in the hippocampus. Moreover, WNT3A stimulation enhanced T-type current in cultured thalamic neurons. Together, our data indicate that the LEF1/beta-catenin complex regulates transcription of Cacna1g and uncover a novel function for beta-catenin in mature neurons. We propose that beta-catenin contributes to neuronal excitability not only by a local action at the synapse but also by activating gene expression in thalamic neurons.
Wisniewska
Marta B
MB
International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland. mwisniew@iimcb.gov.pl
Misztal
Katarzyna
K
Michowski
Wojciech
W
Szczot
Marcin
M
Purta
Elzbieta
E
Lesniak
Wieslawa
W
Klejman
Monika E
ME
Dabrowski
Michal
M
Filipkowski
Robert K
RK
Nagalski
Andrzej
A
Mozrzymas
Jerzy W
JW
Kuznicki
Jacek
J
D000367:Age Factors; D000818:Animals; D020747:Calcium Channels, T-Type / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000737:chemistry / Q000502:physiology*; D008297:Male; D051379:Mice; D009474:Neurons / Q000502:physiology*; D051381:Rats; D013569:Synapses / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013788:Thalamus / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D051176:beta Catenin / Q000737:chemistry / Q000502:physiology*
C495267:CTNNB1 protein, mouse; C498197:Cacna1g protein, mouse; D020747:Calcium Channels, T-Type; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D051176:beta Catenin