The WWOX Gene Influences Cellular Pathways in the Neuronal Differentiation of Human Neural Progenitor Cells

Abstract

The brain is the most functionally organized structure of all organs. It manages behavior, perception and higher cognitive functions. The <i>WWOX</i> gene is non-classical tumor suppressor gene, which has been shown to have an impact on proliferation, apoptosis and migration processes. Moreover, genetic aberrations in <i>WWOX</i> induce severe neuropathological phenotypes in humans and rodents. The aim of the present study was to investigate in detail the impact of <i>WWOX</i> on human neural progenitor cell (hNPC) maintenance and how depletion of <i>WWOX</i> disturbs signaling pathways playing a pivotal role in neuronal differentiation and central nervous system (CNS) organogenesis. hNPC with a silenced <i>WWOX</i> gene exhibited lowered mitochondrial redox potential, enhanced adhesion to fibronectin and extracellular matrix protein mixture, downregulation of MMP2/9 expression and impaired 3D growth. Global transcriptome analysis using cap analysis of gene expression (CAGE) found that <i>WWOX</i> downregulation significantly changes the expression of multiple genes engaged in cytoskeleton organization, adhesion, cell signaling and chromatin remodeling. The massive changes in gene expression caused by <i>WWOX</i> silencing may strongly affect the differentiation and migration of neurons in organogenesis, brain injury, cancerogenesis or neurodifferentiation. <i>WWOX</i> gene appears to be an important regulator of neural tissue architecture and function.