Wnt/β-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders

Abstract

Wnt signaling is a fundamental pathway in embryogenesis which is evolutionary conserved from metazoans to humans. Much of our understanding of Wnt signaling events emerged from key developmental studies in drosophila, zebra fish, xenopus, and mice. Considerable data now exists on the role of Wnt signaling beyond these developmental processes and in particular its role in health and disease. The focus of this special issue is on Wnt/β-catenin and its diverse physiological cell signaling pathways in neurodegenerative and neuropsychiatric disorders. This special issue is composed of six reviews and two original articles selected to highlight recent advances in the role of Wnt signaling in CNS embryonic development, in adult brain function, in neurodegenerative conditions such as Alzheimer's disease, schizophrenia, NeuroAIDS, and in gliomas. The finding that β-catenin can translocate to the nucleus where it binds to TCF/LEF transcription factors to regulate target gene expression was a seminal observation that linked β-catenin/LEF to T cell development and differentiation. We also provide a nostalgic look on recent advances in role of Wnts in T cell development and maturation. These reviews highlight the extensive body of work in these thematic areas as well as identify knowledge gaps, where appropriate. Understanding Wnt function under healthy and diseased conditions may provide a therapeutic resource, albeit it a challenging one, in diseases where dysfunctional and/or diminished Wnt signaling is a prominent player in the disease process.

Fig. 1

Wnt signaling. A simplified diagram ofWnt β-catenin dependent and independent signaling: a β-catenin-dependent pathway: β-catenin dependent signaling is initiated by binding of Wnts to frizzled seven transmembrane receptors. This binding leads to a series of events culminating in deactivation of a multi-protein β-catenin destruction complex. Subsequently, hypophosphorylated β-catenin translocates to the nucleus where it binds TCF/LEF transcription factors to regulate gene expression. b Wnt β-catenin independent/calcium pathway. Wnts binding to frizzled lead to calcium influx, which activates calmodulin-dependent protein kinase II and NFAT. NFAT binds to its cognate target gene to regulate gene expression. c Wnt β-catenin independent/planar cell polarity pathway: Wnt binding to frizzled leads to Rac/Rho activation and subsequently to activation of kinases such as JNK that modulates cytoskeletal rearrangements. This figure is adapted from (Henderson and Al-Harthi 2011) and (Mulligan and Cheyette 2012)

Fig. 2

Role of Wnt signaling in the adult brain. The diagram highlights several key features of Wnt involvement in homeostatic activities of the adult brain, including events in cellular migration and communication, survival, neurogenesis, synaptic plasticity, and repair