Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/β-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/β-catenin signaling in ASD. First, we discuss that Wnt/β-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/β-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/β-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.

Keywords: Wnt/β-catenin signaling; autism spectrum disorders (ASD); chromatin remodeling proteins; synaptic dysfunction; transcription.