Wnt/β-catenin signaling stimulates the expression and synaptic clustering of the autism-associated Neuroligin 3 gene.
Matías A MedinaVíctor M AndradeMario O CaracciMiguel E AvilaDaniela A VerdugoMacarena F VargasGiorgia D UgarteAriel E ReyesCarlos OpazoGiancarlo V De FerrariPublished in: Translational psychiatry (2018)
Synaptic abnormalities have been described in individuals with autism spectrum disorders (ASD). The cell-adhesion molecule Neuroligin-3 (Nlgn3) has an essential role in the function and maturation of synapses and NLGN3 ASD-associated mutations disrupt hippocampal and cortical function. Here we show that Wnt/β-catenin signaling increases Nlgn3 mRNA and protein levels in HT22 mouse hippocampal cells and primary cultures of rat hippocampal neurons. We characterized the activity of mouse and rat Nlgn3 promoter constructs containing conserved putative T-cell factor/lymphoid enhancing factor (TCF/LEF)-binding elements (TBE) and found that their activity is significantly augmented in Wnt/β-catenin cell reporter assays. Chromatin immunoprecipitation (ChIP) assays and site-directed mutagenesis experiments revealed that endogenous β-catenin binds to novel TBE consensus sequences in the Nlgn3 promoter. Moreover, activation of the signaling cascade increased Nlgn3 clustering and co- localization with the scaffold PSD-95 protein in dendritic processes of primary neurons. Our results directly link Wnt/β-catenin signaling to the transcription of the Nlgn3 gene and support a functional role for the signaling pathway in the dysregulation of excitatory/inhibitory neuronal activity, as is observed in animal models of ASD.
Keyphrases
- autism spectrum disorder
- cell proliferation
- transcription factor
- single cell
- intellectual disability
- stem cells
- attention deficit hyperactivity disorder
- binding protein
- signaling pathway
- dna methylation
- high throughput
- genome wide
- epithelial mesenchymal transition
- gene expression
- cerebral ischemia
- induced apoptosis
- cell adhesion
- spinal cord
- crispr cas
- oxidative stress
- rna seq
- poor prognosis
- dna damage
- brain injury
- blood brain barrier
- protein protein
- cell therapy
- mesenchymal stem cells
- working memory
- genome wide analysis