UCSF

The Role of Wnt Signaling Proteins in Neurodevelopment and Psychiatric Susceptibility

Robert Stanley

Abstract

Proper regulation of cell signaling pathways is required for normal neurodevelopment. Dysfunction in signaling can lead to problems in the development of the brain and increased susceptibility to develop psychiatric disorders. Many components are required to act in concert in multiple intersecting pathways, and mutations in these components can lead to aberrant signaling. Modern human genetics is increasingly identifying genes and gene mutations associated with psychiatric risk via genome-wide sequencing of patients with psychiatric disorders. Once specific genes and their mutations are identified as possible contributors to disease, experimental assays are required to determine the functionality of these genes and their variants in neurodevelopment and signaling.

The scaffolding protein Dix-Domain Containing 1 (Dixdc1) is a positive regulator of Wnt-/β-catenin signaling that interacts with the psychiatric risk gene Disrupted in Schizophrenia 1 (Disc1). We have a utilized a Dixdc1 knock-out mouse line to help determine functions of this gene in neurodevelopment. Using cultured hippocampal neurons and tissue sections from intact brains expressing GFP in cortical neurons, we have interrogated what effect deletion of Dixdc1 has on the development of dendrites, dendritic spines, and synapses in pyramidal neurons of the forebrain. In addition, using sequencing data from patient samples of three different psychiatric disorders (ASD, Schizophrenia, and Bipolar Disorder) we have identified a set of rare missense mutations in the Dixdc1 locus that are present in patients with these diseases. These variants were then functionally tested using several neurodevelopmental and canonical Wnt/Beta-catenin signaling assays.

Our results show that Dixdc1 is required for proper development of spines- both in their quantity and maturation- and excitatory synapses in forebrain pyramidal neurons. There appears to be no effect on dendrite complexity (in a mixed genetic background) or on inhibitory synapse numbers. Additionally, mutant versions of Dixdc1 found in ASD patient samples that have aberrant Wnt signaling are unable to rescue neurodevelopmental phenotypes in KO neurons, while some of these variants that are hyperactive for Wnt/β-catenin signaling have dominant negative effects when expressed in wild type neurons.