Physiological Role of β-Catenin/TCF Signaling in Neurons of the Adult Brain

Abstract

Wnt/β-catenin pathway, the effectors of which are transcription factors of the LEF1/TCF family, is primarily associated with development. Strikingly, however, some of the genes of the pathway are schizophrenia susceptibility genes, and the proteins that are often mutated in neurodegenerative diseases have the ability to regulate β-catenin levels. If impairment of this pathway indeed leads to these pathologies, then it likely plays a physiological role in the adult brain. This review provides an overview of the current knowledge on this subject. The involvement of β-catenin and LEF1/TCF factors in adult neurogenesis, synaptic plasticity, and the function of thalamic neurons are discussed. The data are still very preliminary and often based on circumstantial or indirect evidence. Further research might help to understand the etiology of the aforementioned pathologies.

Beta-catenin in schizophrenia: Possibly deleterious novel mutation

“…The list included: The catenin CTNNB1 is a major player in the WNT pathway and accomplishes two roles inside the cell: as a transcriptional activator for transcription factor families like lymphoid enhancerbinding factor 1/T-cell transcription factor (LEF1/TCF) family and as a protein that binds to cadherins at adherens junctions, thus stabilizing the cytoskeleton and taking part in the structure of synapses (Logan and Nusse, 2004;Wisniewska, 2013). CTNNB1 with the transcription factors LEF1/TCF initiate expression of genes important in many aspects of development, including neurogenesis and synaptic plasticity (Wisniewska, 2013). CTNNB1 protein levels were found to be decreased in the hippocampus of schizophrenic patients in a post-mortem study (Cotter et al, 1998).…”

“…GSK3B negatively regulates the activity of CTNNB1 in the so-called canonical WNT pathway, by phosphorylating it; phosphorylated CTNNB1 undergoes degradation in the proteasome (Logan and Nusse, 2004;Wisniewska, 2013). This kinase is also implicated in regulation of neuronal cytoskeleton, by phosphorylating microtubuleassociated proteins (Goold et al, 1999;Wood-Kaczmar et al, 2009).…”

“…WNT2B and WNT7B are members of the WNT family of signaling factors, binding to the receptors Frizzled, therefore activating the canonical and non-canonical WNT pathways, as well as binding to some types of receptors tyrosine kinase; all these events are implicated in neurogenesis, synaptic plasticity and regulation of neuronal cytoskeleton (reviewed in Logan and Nusse, 2004;Singh, 2013;Wisniewska, 2013). These two ligands in particular are expressed in the dorsal midline structures of the developing human diencephalon (Abu-Khalil et al, 2004).…”

“…The WNT pathway plays, among other roles in development, a role in establishment of the LR axis of the body (Kitajima et al, 2013) and of the brain, at least of the diencephalon (Husken and Carl, 2013). It is also important for the functioning of the adult brain (Wisniewska, 2013). Moreover, the pathway is implicated in the pathogenesis of schizophrenia (Panaccione et al, 2013;Singh, 2013;Peng et al, 2014).…”

The Role of Wnt/β-Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target?

“…It has also been confirmed to modulate neurogenesis, neural differentiation, synapse development, and plasticity in the central nervous system (CNS) [11,12]. Wnt signaling is also associated with a number of CNS disorders, such as Alzheimer's disease, schizophrenia, and mood disorders [13][14][15].…”