Anatomic and molecular features observed in the brains of individuals with autism suggest that abnormalities in early embryonic development underlie the development of autism. Mutations in a gene called CHD8 are the most commonly identified mutations associated with autism.  How CHD8 influences the disorder remains unknown, but observations that children with autism and CHD8 mutations have abnormally large heads (macrocephaly) support the possibility that CHD8 functions in regulating brain growth during development.

Anjen Chenn and his team at the University of Illinois at Chicago previously found that CHD8 can negatively regulate the WNT/beta-catenin pathway, a cell signaling pathway that plays an important role in normal brain development. Chenn’s work showed that overactivity of beta-catenin signaling leads to abnormal enlargement of the cerebral cortex¹, ², changes in the relative numbers of different kinds of neurons in the cerebral cortex, and abnormalities in where these neurons send their axons³, features observed in postmortem studies of brains of children with autism⁴, ⁵. These studies suggest that CHD8 regulation of WNT/beta-catenin signaling may underlie a developmental etiology for autism.

Chenn and his team plan to use mouse models to examine the hypothesis that CHD8 regulation of beta-catenin signaling functions to regulate cerebral cortical growth. Their experiments aim to test the role of CHD8 in embryonic cerebral cortical development and explore the interactions between CHD8 and beta-catenin signaling in cortical development.

Although the genetics of autism suggest myriad rare genetic etiologies, the frequently observed macrocephaly in children with the disorder suggests common abnormalities of critical neurodevelopmental events such as the regulation of the proper number and position of neurons in the cerebral cortex. These can lead to abnormalities of higher-order neuronal circuit formation in autism. Understanding the neurodevelopmental function of CHD8 and identifying its downstream targets will help integrate our understanding of neural development with the complex genetics of autism.