The role of chromatin remodelling factors in cerebellar development and autism

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Autism can be a devastating condition for which no suitable treatment exists. Autism affects some of the core behavioural features an individual needs to function in society, namely social interaction and both verbal and non-verbal communication. Children affected by autism often demonstrate restricted, repetitive patterns of behaviour and interests. The number of individuals diagnosed with Autism Spectrum Disorder (ASD) has increased dramatically over the last decade and current estimates suggest that up to 1/110 of the population may be affected. The causes of autism are not known and without this knowledge, there is limited hopes of finding novel ways of treating this condition or improving the lives of autistic children. Autism is a complex genetic condition; many genetic abnormalities that can predispose a child to autism have been identified, but our knowledge on how these genetic risk factors can cause changes during brain development to result in autistic behaviour is extremely limited. Studies in autistic children have suggested that the growth of certain parts of the brain might to be altered during development. The part of the brain that appears to be affected most often is the cerebellum. The cerebellum controls movement, but also functions as an important modulator of other parts of the brain, including regions involved in social cognition and language development. It is not known how these defects in the cerebellum arise, nor is it known what the effects of cerebellar defects are on behaviours characteristic of autism. Currently, the best way to address this question directly is to study brain development and the behavioural consequences of altered brain development on behaviour in mice that have mutations in autism-associated genes. Our group have been investigating the functions of the CHD7 gene in brain development. CHD7 causes CHARGE syndrome when mutated, a complex human syndrome where children suffer from a range of birth defects in addition to autistic symptoms. We recently identified essential roles for CHD7 in the development and growth of the cerebellum. When CHD7 is mutated, we observe defects in specific areas of the cerebellum that have been linked to autism. The aim of this project will be to identify the exact causes of these defects and to uncover the specific processes that are defective when CHD7 is absent. This knowledge may help define specific therapies to target these processes in the future.In addition, we have used the powerful genetic methods available in the mouse to produce mutants in which CHD7 is removed specifically from the developing cerebellum. These new mouse mutants will enable us to determine to what extent these cerebellar defects cause autistic symptoms. Furthermore, we will take the same approach to determine the function of a related gene called CHD8, which was recently shown to be very strongly associated with autism in the human population, but without any of the birth defects typical of CHARGE syndrome. These studies will allow us to hone in on the specific causes of autism. This research will allow us to find answers to several important questions in autism research. We will identify the reasons why mutations in CHD7 and CHD8 can cause problems during brain development, the exact mechanisms whereby these factors control growth and development of the cerebellum and we will determine to what extent cerebellar defects are responsible for some of the core behavioural symptoms characteristic of autism. Taken together, our research will significantly improve our understanding of the causes of autism and define the importance of cerebellar defects in the development of autism. Our findings will create an important source of knowledge upon which future attempts to predict, diagnose, and possibly treat specific aspects of autism could be based.