Examining The Roles of TBR1 and AUTS2 in Producing Autism Spectrum Disorders and Brain Malformations
Human brain development is a highly organized and intricate process. When all goes well, developmental programs produce extraordinary structural and functional complexity – allowing healthy cognition, communication skills, and sensorimotor capabilities. But when development goes awry, for example, due to a genetic mutation, defects of these programs cause neuropsychiatric disorders - such as autism, epilepsy and intellectual disability - often with devastating consequences for individuals, families, and society.
Dr. Robert Hevner
Of central significance in autism, and associated co-morbidities, are the functions of the TBR1 and AUTS2 genes. De novo mutations in TBR1 and AUTS2 are now well established as causes of "idiopathic" (non-inherited) autism spectrum disorders. Understanding dysfunctions in the TBR1 and AUTS2 genes is pivotally important to Dr. Hevner’s research on autism and associated defects, including the AUTS2 syndrome associated with brain malformations, intellectual disability, and autistic personality traits. During embryonic development in healthy individuals, TBR1 and AUTS2 proteins are found to colocalize in the cortical preplate, and AUTS2 is also detected in the developing dorsal thalamus, olfactory bulb, inferior colliculus and substantia nigra. Multiple isoforms of the AUTS2 gene may contribute to diverse functions in brain development, and different mutations lead to the development of various developmental disorders as part of AUTS2 syndrome phenotype.
To better understand how AUTS2 mutations affect brain development and function, Dr. Hevner and his group have developed a novel mouse model that effectively replicates human morbidity in precise neuronal locations using a conditional knockout approach. Studies with this model allow Dr. Hevner’s group to understand the progression of autism and structural defects during embryonic development, and subsequently how it translates into behavioral traits.
Dr. Hevner is interested in collaborations involving development of new therapeutics aimed at restoring function in patients with AUTS2 syndrome and other autism spectrum disorders. Similarly, Dr. Hevner is well positioned to help optimize existing treatment regimes to be more effective by understanding the impact of gene dysfunction in individuals with autism.
Stage of Development
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Hevner R. Brain overgrowth in disorders of RTK–PI3K–AKT signaling: A mosaic of malformations. Seminars in Perinatology. 2015;39(1):36-43.
- Sun T, Hevner R. Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nature Reviews Neuroscience. 2014;15(4):217-232.
- Bedogni F, Hodge R, Nelson B, Frederick E, Shiba N, Daza R, Hevner R. Autism susceptibility candidate 2 (Auts2) encodes a nuclear protein expressed in developing brain regions implicated in autism neuropathology. Gene Expression Patterns. 2010;10(1):9-15.
- Bedogni F, Hodge R, Elsen G, Nelson B, Draza R, Beyer R, Bammler T, Rubenstein J, Hevner R. Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proceedings of the National Academy of Sciences. 2010;107(29):13129-13134.
To learn more about partnering with Seattle Children’s Research Institute on this or other projects, please contact:
Dr. Elizabeth Aylward
Director, Office of Science-Industry Partnerships