Dr Thomas Theil
Centre for Discovery Brain Sciences
University of Edinburgh
0131 650 3721
Primary cilium, corticogenesis, radial glial cells, Gli3, Inpp5e
The cerebral cortex is responsible for all higher mental and cognitive functions unique to humans. Disruption of its function underlies a variety of different neurological disorders such as intellectual disability, autism and certain forms of epilepsy. To fulfil its role the cortex requires an enormous variety of different neurons, far more than in any other part of the brain.
This striking degree of neuronal diversity is generated from cortical stem cells during embryonic development. The general aim of our research is to better understand the mechanisms which lead to the generation of these different types of cortical neurons and how cell signalling and transcriptional regulation converge to control cortical neuron formation.
Gli3 zinc finger transcription factor
To address these questions, we are using the mouse as a model organism and we are particularly interested in the role of the Gli3 zinc finger transcription factor. The human GLI3 gene is mutated in a number of syndromes, including Acrocallosal Syndrome (ACS) and Greig cephalopolydactyly Syndrome (GCPS) which can lead to intellectual disability. In our lab, we are characterizing cortical development in Gli3 mutant mice to identify the mechanisms which lead to intellectual disability in GLI3 syndrome patients.
Our studies revealed that Gli3 is not only a negative regulator of Sonic hedgehog signalling but also regulates the expression of several Fgf, Bmp and Wnt signalling molecules. Using reporter gene and DNA binding assays we showed that direct interactions between Gli3 and these signalling factors underlie cortical development. Furthermore, we perform gene expression profiling experiments to identify Gli3 target genes and Gli3 interactions with other transcription factors essential for cortical development.
Role of the primary cilium in cortical stem cells
The primary cilium acts as a signalling hub integrating signalling pathways during embryonic development and tissue homeostasis. Due to their prominent role in cell signalling, cilia are ideal candidates to control the development of cortical stem cells but surprisingly little is known about these roles.
We investigate cilia functions in cortical stem cells using mice mutant for the Inpp5e gene that is essential for cilial signalling and cilia stability. We are systematically characterizing the formation of cortical stem and progenitor cells and their proliferation and differentiation in Inpp5e mutants. Elucidating the mechanisms and signals that primary cilia use to control cortical stem cell development will help us to understand how cortical stem and progenitor cells are maintained but are also able to produce neurons in sufficient numbers and of the appropriate type.