WNT-Frizzled signalling and the many paths to neural development and adult brain homeostasis

Abstract

The regulation of brain development and function is the result of complex cell-restricted and temporal expression profiles directed by signaling networks constantly imposing exquisite regulatory control on many genes at any one moment within a cell. The ultimate outcome is a genetically controlled balancing act where expression profiles of these hundreds of genes result in cellular proliferation, differentiation and the ultimate choice between long-term survival and apoptosis. During embryonic development there is a massive expansion of neurons and glia, which is balanced with programmed cell death as the brain matures and remodels. As developing brain cells differentiate, they migrate toward the region where they will ultimately seek out interactions with other cells and perform their specialized tasks. Although a number of signaling pathways have been shown to contribute to various processes allowing the maintenance of normal neurogenesis, the precise signaling machinery necessary for modulating the maintenance of both the neuroblast and differentiated neuronal population, and regulating transition between the two, is still being solved. Not surprisingly, the Wnt signaling pathway is important in regulating neural development but also appears to be involved in adult neurogenesis and some brain disorders. Here, we review key findings showing the pivotal nature of Wnt-Frizzled (FZD) signaling in neurogenesis as revealed by a number of molecular genetic studies using mice and other model organisms. We also review the current literature on the role of the Wnt pathway in the generation of brain cancers, particularly the most common primitive neuroectodermal tumors in childhood, neuroblastomas, and in neurodegenerative diseases such as Alzheimer's disease.