Many types of neuropsychiatric conditions, including Autism spectrum disorders (ASD), bipolar disorder, and schizophrenia, have a significant genetic component, although they are generally thought to involve a complex mix of interacting genes. However, some of these disorders can also be driven by mutations in single genes, suggesting that these loci have central and pivotal roles in the neurodevelopmental underpinnings of the disease. One such essential genetic factor, AUTS2, was originally discovered as disrupted in a pair of autistic twins, and AUTS2 mutations have since been more generally linked to syndromic forms of intellectual disability as well as epilepsy, schizophrenia and other disorders. Genome-wide association studies (GWAS) have further linked AUTS2 to the inheritance of bipolar disorder, major depression, alcohol consumption, and susceptibility to heroin addiction. This single gene is thus implicated in an exceptionally broad range of neuropsychiatric disorders with profound societal impact. However, the cellular and developmental functions of this important gene are not understood. We have discovered a mouse mutation, called 16Gso, which dysregulates certain transcripts arising from the Auts2 gene during critical times in development; despite this partial loss-of-function, 16Gso mutants display morphological, behavioral, and brain structural abnormalities that model human AUTS2-linked phenotypes strikingly well. Our developmental studies have revealed the loss of critical neuronal populations in 16Gso mutants during early postnatal life; the loss of these neurons could well explain many aspects of the 16Gso phenotype, and similar neuronal abnormalities may underlie human AUTS2-linked symptoms as well. Thus, clues provided by analysis of the 16Gso mutant could suggest new avenues for diagnosis and treatment of human AUTS2-linked disease. This proposal is focused on developing this mouse model, and specifically, defining the role of Auts2 in the 16Gso phenotype using genetic complementation tests. To achieve this goal we will obtain Auts2-/- targeted mutants, and compare their morphology, behavior, and molecular phenotypes to 16Gso homozygotes as well as 16Gso/Auts2- compound heterozygotes. Together these mutant animals will provide important tools for analysis of Auts2 neurodevelopmental function in a mammalian model system.
Mutations in the human AUTS2 gene have been implicated in an exceptionally broad array of neuropsychiatric disorders with profound societal impact, and a deeper understanding of AUTS2 neurodevelopmental functions could be central to design of new methods for diagnosis and treatment. However, the molecular and developmental functions of this gene are poorly understood. This proposal aims to develop an existing mouse model that dysregulates Auts2 gene expression and recapitulates many of the symptoms exhibited by human AUTS2 patients, with the goal of understanding the neurodevelopmental role of this important gene.
