We have identified a novel single nucleotide polymorphism (SNP) in the DACT1 locus that alters an evolutionarily conserved amino acid in a conserved domain of the protein. We hypothesize that this SNP, which tracks with the diagnosis of autism in an affected family, alters protein function in developing neurons to cause the disease. We have developed a model system in which to study functions of the corresponding protein in early postnatal forebrain neurons, a cell type that is likely to be relevant to autism pathogenesis. This system uses a novel conditional knock-out mouse line generated in my laboratory together with established methods for studying the maturation of hippocampal neurons (HCNs) in culture.
Our specific aims are to answer the following questions: 1. Does loss of Dact1 have developmental consequences in forebrain neurons? 2. Does the autism-variant Dact1 protein have different biochemical properties than the wild type Dact1 protein? 3. Do the wild type and autism-variant Dact1 proteins display functional differences during neural development? This is an exploratory grant to the National Institute of Mental Health to support the laboratory of a young investigator who is a psychiatrist trained as a basic scientist. Our goal is to rapidly exploit this opportunity to investigate functions of a wild type and an autism-linked variant Dact1 protein during neural development. It is hoped that this will lead to a major area of research in this laboratory that will contribute importantly to progress in the autism field.
Autism afflicts as many as 1 in 150 children in the United States and is a behavioral disorder with a high negative impact on individuals, their families, and our society. Understanding its biological basis in order to improve diagnosis and treatment are high priorities for public health. This project investigates a gene mutation discovered in a family with autism and how this leads biologically to the disease.
| Arguello, Annie; Cheyette, Benjamin Nr (2013) Dapper Antagonist of Catenin-1 (Dact1) contributes to dendrite arborization in forebrain cortical interneurons. Commun Integr Biol 6:e26656 |
| Arguello, Annie; Yang, XiaoYong; Vogt, Daniel et al. (2013) Dapper antagonist of catenin-1 cooperates with Dishevelled-1 during postsynaptic development in mouse forebrain GABAergic interneurons. PLoS One 8:e67679 |
| Okerlund, Nathan D; Cheyette, Benjamin N R (2011) Synaptic Wnt signaling-a contributor to major psychiatric disorders? J Neurodev Disord 3:162-74 |
| Okerlund, Nathan D; Kivimäe, Saul; Tong, Cheuk Ka et al. (2010) Dact1 is a postsynaptic protein required for dendrite, spine, and excitatory synapse development in the mouse forebrain. J Neurosci 30:4362-8 |
