Professor of Developmental Neurobiology
Our main focus areas are:
Functions and mechanisms of CHD7 in cerebellar and frontal cortex development, Neurodevelopmental roles of CHD8 and associated chromatin remodelling factors, Investigating how microglia respond to environmental factors during brain development, Unbiased approaches to identify distal regulatory elements in primary cerebellar granule neuron progenitors, Creating new mouse models for aggressive medulloblastoma subtypes.
Development of the cerebellum
A major focus of the laboratory has been to understand how mammalian cerebellum develops. We are examining the mechanisms necessary for establishing and maintaining early cerebellar progenitors during regionalisation of the embryonic neural tube and the mechanisms that regulate the proliferation and differentiation of cerebellar granule neuron progenitors during early postnatal life (Yu et al. (2011) Development 138: 2957-2968). The cerebellum 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 and is associated with a number of important neurodevelopmental disorders, including autism (Basson & Wingate (2013) Front Neuroanat. 7:29). Our research therefore, has important implications for understanding the genetic and epigenetic causes of cerebellar hypoplasia, ataxia, autism and cerebellar tumours (medulloblastoma).
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 (Basson et al. (2008) Development 135: 889-898). These findings led to the hypothesis that epigenetic alterations that affect FGF gene expression and signalling in the embryonic mid-hindbrain region will be associated with vermis hypoplasia in the human population.
Image: The mouse cerebellum in wholemount (left), sagittal section (middle) and after immunohistochemistry for PCP2 to visualize developing Purkinje neurons in a postnatal day 7 cerebellum.
Chromatin remodelling factors in neural development and autism: CHD7 and CHARGE syndrome
The CHD7 gene is mutated in human CHARGE syndrome, a rare, but devastating syndrome that affects multiple organs. CHD7 primarily associates with distal enhancers where it appears to function as a “rheostat” that fine-tunes the expression levels of developmentally important genes.
Image: CHD7 is associated with distal gene enhancers, where it interacts with other chromatin remodelling complexes and presumably affects gene expression by remodelling chromatin.
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. Using these models, we recently identified CHD7 as a key regulator of homeobox gene expression in the developing neural tube and found that de-regulated homeobox gene expression was associated with reduced FGF gene expression and signalling. This finding led to a collaboration with Conny van Ravenswaaij-Arts in the Netherlands, which identified cerebellar hypoplasia in a significant proportion of CHARGE syndrome patients (Yu et al. (2013) eLife 2:e01305, Basson (2014) Rare Diseases 2: e28688).
We have identified additional roles for CHD7 in neural stem cell quiescence in the adult hippocampus (Jones et al. (2015) Stem Cells. 33:196-210) and cerebellar granule neuron progenitors. We are currently working on identifying the mechanisms whereby the loss of CHD7 results in these defects.
Chromatin remodelling factors in neural development and autism: CHD8 and autism
Mutations in CHD8 have been implicated in a subtype of autism characterised by intellectual disability, macrocephaly, and additional craniofacial and gastro-intestinal defects. Recent estimates suggest that autism spectrum disorders affect approximately 1/110 children in the UK and up to 1/88 in the USA. We have produced new mouse and zebrafish models to investigate the functions of CHD8 in neural development and disease.