Principal Investigator: Dr M. Albert Basson
The Basson laboratory studies the function of signalling regulators and chromatin remodelling factors in development in order to uncover the mechanisms underlying congenital disease. The group is primarily interested in neurodevelopmental conditions.
Every specialised cell in the body contains exactly the same genetic information in the form of the genome. Thus, the mechanisms that control cellular differentiation and maintain cellular identity operate at a level “above the genetic code”. These epigenetic mechanisms establish the complement of gene expression that ultimately determines cell fate.
During embryonic development, when cell fates are first determined, cell identity is initially specified in response to signals from the local micro-environment. Many of these signals take the form of secreted growth factors.
The Basson lab has been particularly interested in Receptor Tyrosine Kinase (RTK) signalling. Growth factors like FGFs are used repeatedly in many development contexts and regulate somatic stem cell homeostasis and regeneration in the adult organism.
Our work has demonstrated central roles for Sprouty genes in the regulation of RTK signalling. We have found that removal of these genes can have major impacts on the development of several essential organs, including the kidney, thymus, parathyroid, sensory ganglia, cardiovascular system, midbrain and cerebellum.
Several other organs have been added to this list through the work of a number of other colleagues and independent groups. In addition, in collaboration with Dr. Andrew Brack’s group at Harvard, we have found that Sprouty1 is essential for normal function of muscle stem cells in the adult organism.
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Current research projects
Development of the cerebellum
A major focus of the laboratory has been to understand how FGF signalling is regulated during development of the mammalian cerebellum. The cerebellum is the part of the brain that is essential for fine motor control and cerebellar defects can result in ataxia.
In addition, the cerebellum has been implicated in cognition and cerebellar hypoplasia is associated with a number of important neurodevelopmental disorders, including autism. By manipulating the levels of FGF signalling during brain development in the mouse, we have identified a specific region of the cerebellum, the vermis, which is particularly sensitive to reductions in FGF signalling. We predict that similar defects in FGF signalling should be associated with vermis hypoplasia in the human population.
Read about the groundbreaking study, The Cerebellum and Autism, which sheds light on the various regulatory mechanisms at play during the development of the mammalian cerebellum, and the relevance of this exciting research to autism and CHARGE syndrome.
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Chromatin remodelling factors in neural development and autism
Recently, the lab has become interested in members of the CHD chromatin remodeling factors, CHD7 and CHD8. The CHD7 gene is mutated in human CHARGE syndrome, a rare, but devastating syndrome that affects multiple organs.
In collaboration with Pete Scambler’s group at the UCL Institute for Child Health, we have developed mouse models, which allow us to study the developmental causes of brain defects associated with this syndrome. CHD7 primarily associates with distal enhancers where it appears to function as a “rheostat” that fine-tunes the expression levels of developmentally important genes.
We are currently working on identifying the mechanisms whereby the loss of CHD7 result in neurodevelopmental defects
Image: CHD7 is associated with distal gene enhancers, where it interacts with other chromatin remodelling complexes and presumably affects gene expression by remodelling chromatin.
Mutations in CHD7, and a related factor CHD8, with which it interacts, have been implicated in autism. Recent estimates suggest that autism spectrum disorders affect approximately 1/110 children in the UK and up to 1/88 in the USA.
Our future aims
To understand the roles of CHD7 and CHD8 in neural development;
To elucidate the mechanisms whereby CHD7 and CHD8 function to fine-tune gene expression;
To determine the behavioural consequences of specific cerebellar defects, especially as it relates to autism
Dr Graham Kenny
Clinical Research Fellow
Dr Danielle Whittaker
Mr Sahrunizam Kasah
Mr Nemanja Saric
Ms Kimberley Riegman
Contact for further information
Tel: +44 (0)20 7188 1804