Autism encompasses a range of cognitive and behavioral characteristics, and studies suggest that certain genetic abnormalities are common in individuals with autism. A major challenge is to link these genetic abnormalities with the behavioral features of autism, such as social deficits and anxiety. Gil Levkowitz and his colleagues are tackling basic questions concerning the development and function of the hypothalamus, an important yet understudied brain region.
The hypothalamus is involved in helping animals adapt to emotional and physiological challenges, and it regulates fundamental body functions, including sleep, blood pressure, temperature, appetite, metabolism, stress responses and social behavior. In 2012, Levkowitz demonstrated in zebrafish that the autism-associated gene A2BP1 (also known as RBFOX1) is involved in stress hormone synthesis and anxiety-like responses1.
A2BP1 protein is involved in a gene regulation process known as alternative splicing, and it appears to be expressed at lower levels in the brains of people with autism than in controls. Lower expression of A2BP1 is also associated with dysregulated splicing of target genes in individuals with autism. Levkowitz and his colleagues have found that one such A2BP1 target, PAC1, is implicated in the activation and termination of stress and anxiety-like responses in zebrafish.
Levkowitz and his colleagues employed a genome editing approach to generate two zebrafish mutants. The first disrupts the function of the A2BP1 gene, and the second disrupts an alternatively spliced PAC1 exon (known as the ‘hop cassette’), the splicing of which is normally regulated by A2BP1. The researchers’ goal is to understand how disruptions in A2BP1 and/or its splicing target PAC1, dubbed ‘the hopless fish’ mutant, may be connected with autism and hypothalamic function.