Wnt/β-catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

Abstract

Canonical Wnt signaling, which is transduced by β-catenin and lymphoid enhancer factor 1/T cell-specific transcription factors (LEF1/TCFs), regulates many aspects of metazoan development and tissue renewal. Although much evidence has associated canonical Wnt/β-catenin signaling with mood disorders, the mechanistic links are still unknown. Many components of the canonical Wnt pathway are involved in cellular processes that are unrelated to classical canonical Wnt signaling, thus further blurring the picture. The present review critically evaluates the involvement of classical Wnt/β-catenin signaling in developmental processes that putatively underlie the pathology of mental illnesses. Particular attention is given to the roles of LEF1/TCFs, which have been discussed surprisingly rarely in this context. Highlighting recent discoveries, we propose that alterations in the activity of LEF1/TCFs, and particularly of transcription factor 7-like 2 (TCF7L2), result in defects previously associated with neuropsychiatric disorders, including imbalances in neurogenesis and oligodendrogenesis, the functional disruption of thalamocortical circuitry and dysfunction of the habenula.

Keywords: TCF7L2; Wnt pathway; beta-catenin; brain development; habenula; mental disorders; neurogenesis; oligodendrogenesis; postmitotic differentiation; thalamus.

Figure 1

Canonical Wnt/β‐catenin and divergent signaling pathways. The binding of a Wnt ligand to a Frizzled receptor and LRP5/6 co‐receptor, followed by the recruitment of DVL to the receptor complex, leads to translocation and inhibition of the destruction complex, which consists of the kinase GSK3α/β, Adenomatous Polyposis Coli (APC) and Axin. The phosphorylation of β‐catenin by GSK3α/β in the active destruction complex primes this protein for proteasomal degradation (not shown). Upon inhibition of the complex, β‐catenin accumulates in the cytoplasm and translocates into the nucleus where it activates gene transcription as a co‐activator of LEF1/TCFs. This canonical pathway can branch downstream (a) GSK3α/β inhibition (e.g., to slow protein degradation during mitosis, activate the mTOR pathway, or stabilize the cytoskeleton), (b) β‐catenin stabilization (e.g., to stabilize cell adhesion with cadherins or facilitate the assembly of PDZ domain‐containing proteins), and (c) β‐catenin nuclear translocation (to activate gene transcription by interacting with nuclear receptors, FOXO and other transcription factors).

Figure 2

Location of single nucleotide polymorphisms (SNPs) in the human TCF7L2 gene. Representative intron–exon structure of the TCF7L2 gene. Long introns are represented by a double slash. Blue boxes indicate the alternatively spliced exons, blue arrows represent alternative transcription start sites. Important protein domains are marked by red boxes: β‐catenin binding domain, and DNA binding domain ‐ HMG‐box. Black arrows indicate the location of SNPs or mutations.

Figure 3

Role of Wnt/β‐catenin signaling and TCF7L2 in neurogenesis and gliogenesis in the neocortex. The process of developmental neurogenesis and gliogenesis in the neocortex is opposite to the temporal gradient of Wnt signaling (shown in yellow). Genetic manipulation to downregulate Wnt/β‐catenin signaling causes premature neurogenic divisions of uncommitted progenitors (RG) and a shorter time of neurogenesis as a consequence of precocious astrogenesis. Wnt/β‐catenin signaling inhibits oligodendrocyte precursor cell (OPC) differentiation. This is antagonized by interactions between TCF7L2 and the Kaiso co‐repressor. TCF7L2 interacts with the SOX10 to promote the further differentiation of iOL into mOL in a β‐catenin‐independent manner. Steps in this process that were shown to be activated or inhibited by Wnt/β‐catenin signaling or TCF7L2 are indicated in green with arrows and red bar‐headed lines, respectively. GP, glial progenitor

Figure 4

Role of TCF7L2 in the developing thalamus and habenula. Early knockout of Tcf7l2 impairs segregation of cells in the thalamo‐habenular primordium (upper and middle panel), and disrupts axon growth and regional cell identities (middle panel). Conditional postnatal knockout of Tcf7l2 impairs intrinsic excitability of thalamo‐cortical relay neurons (bottom panel).