Perturbed cortical patterning in autism
Seattle Children’s Research Institute – University of Washington
Autism has been linked to mutations involving many genes and to various environmental factors. But how do these diverse factors lead to the common social, communication and behavioral changes that are characteristic of autism spectrum disorders? Recent studies of postmortem brain tissue from individuals who had autism suggest that disturbances of cerebral cortex patterning may be a ‘final common pathway’ and unifying feature of the brain in autism.
Patterning is the developmental process that divides the cerebral cortex into specialized functional regions, such as visual, auditory, motor and language areas. Disturbances of patterning may lead to deficiency or abnormal development of functional regions, and autism may be the manifestation of certain types of patterning defects, mainly involving the frontal lobe.
Robert Hevner and his colleagues at Seattle Children’s Research Institute aim to elucidate the molecular mechanisms of cortical patterning, using mice as a model system. Like humans, mice have a cerebral cortex that is subdivided into specialized functional regions. Hevner and his colleagues have already found that cortical patterning is regulated in the embryonic brain by a cascade of transcription factors expressed at successive stages of neuronal differentiation. This cascade modulates the development of neurons in each cortical area, to ensure that each neuron has the right molecular composition for its specialized function.
In this study, the researchers plan to examine the molecular correlates of cortical patterning in mice carrying mutations that alter the activity of transcription factors in newly generated neurons. The findings should offer a better understanding of how cortical areas develop, and how different mutations alter the development of specialized cortical areas.
The first report from this study, published in the Proceedings of the National Academy of Sciences in 2010, showed that patterning is initiated by transcription factors in embryonic cortical progenitor cells, and then implemented by a distinct set of transcription factors, including TBR1, as neurons mature in the cortical plate.