Dr Thomas Theil
We are investigating the molecular mechanisms that control cortical patterning.
- 2011: Senior Lecturer, University of Edinburgh
- 2006: Wellcome Trust Fellow, Division of Veterinary Biomedical Sciences, University of Edinburgh, UK
- 1997 - 1998 Postdoc, Medical School, Hannover, Germany
- 1994 - 1997: Postdoc, National Institute for Medical Research, London, UK
- 1994: PhD Natural Sciences, University of Bochum, Germany
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.
- RS MacDonald Seedcorn Fund
- Kerstin Hasenpusch-Theil (Postdoctoral Researcher)
- Alexandra Kehlman (PhD student)
- Prof David Price (University of Edinburgh)
- Dr John Mason (University of Edinburgh)
- Dr Pleasantine Mill (University of Edinburgh)
- Prof Siddharthan Chandran (University of Edinburgh)
- Prof Eric Bellefroid (University Bruxelles)
- Prof Sylvie Schneider-Maunoury (University Paris)
- Prof Benedict Durand (University Lyon)
Ruiz-Reig, N., Andrés, B., Huilgol, D., Grove, E.A., Tissir, F., Tole, S., Theil, T., Herrera, E. and Fairen, A. (2017). Lateral thalamic eminence - a novel origin for mGluR1/lot cells. Cerebral Cortex 27, 2841-2856
Hasenpusch-Theil, K., Watson, J.A. & Theil, T. (2017). Direct interactions between Gli3, Wnt8b and Fgfs underlie patterning of the dorsal telencephalon. Cerebral Cortex 27, 1137-1148
Magnani, D., Morle, L., Hasenpusch-Theil, K., Paschaki, M., Jacobi, M., Schurmans, S., Durand, B. and Theil, T. (2015). The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating patterning of prethalamus and ventral telencephalon. Hum. Mol. Genet. 24, 2578-93
Amaniti, E. M., Fu, C., Lewis, S., Saisani, M., Magnani, D., Mason, J. O. and Theil, T. (2013). Gli3 controls corticothalamic pathfinding by regulating development of the piriform cortex. Cerebral Cortex, doi: 10.1093/cercor/bht244.
Magnani D, Hasenpusch-Theil K, Benadiba C, Yu T, Basson MA, Price DJ, Lebrand C and Theil T. (2012). Gli3 controls corpus callosum formation by positioning midline guideposts during telencephalic patterning. Cerebral Cortex, PMID: 23042737.
Saulnier A, Keruzore M, De Clercq S, Bar I, Moers V, Magnani D, Walcher T, Filippis C, Kricha S, Parlier D, Viviani L, Matson CK, Nakagawa Y, Theil T, Goetz M, Mallamaci A, Marine J-C, Zarkower D and Bellefroid EJ. (2012) The doublesex homolog Dmrt5 is required for the development of the caudomedial cortex in mammals. Cerebral Cortex, PMID: 22923088.
Magnani D, Hasenpusch-Theil K, Theil, T. (2012) Gli3 controls subplate formation and growth of cortical axons. Cerebral Cortex, PMID: 22903314
33) Benadiba C, Magnani D, Niquille M, Morle L, Valloton D, Nawabi H, Ait-Lounis A, Otsmane B, Reith W, Theil T, Hornung J-P, Lebrand C, Durand B. (2012) The Ciliogenic Transcription Factor RFX3 Regulates Early Midline Distribution of Guidepost Neurons Required for Corpus Callosum Development. PLoS Genet 8:e1002606.
Chen, Y., Magnani, D., Theil, T., Pratt, T. & Price, D.J. (2012). Evidence that descending cortical axons are essential for thalamocortical axons to cross the pallial-subpallial boundary in the embryonic forebrain. PLoS One 7, e33105.
Hasenpusch-Theil K, Magnani D, Amaniti EM, Han L, Armstrong D, Theil, T. (2012). Transcriptional Analysis of Gli3 Mutants Identifies Wnt Target Genes in the Developing Hippocampus. Cereb Cortex 22, 2878-93.
Magnani D, Hasenpusch-Theil K, Jacobs EC, Campagnoni AT, Price DJ, Theil T (2010) The Gli3 hypomorphic mutation Pdn causes selective impairment in the growth, patterning, and axon guidance capability of the lateral ganglionic eminence. J Neurosci 30:13883-13894.
Fotaki V, Larralde O, Zeng S, McLaughlin D, Nichols J, Price DJ, Theil T, Mason JO (2010) Loss of Wnt8b has no overt effect on hippocampus development but leads to altered Wnt gene expression levels in dorsomedial telencephalon. Dev Dyn 239:284-296
Szabo NE, Zhao T, Cankaya M, Theil T, Zhou X, Alvarez-Bolado G (2009) Role of neuroepithelial Sonic hedgehog in hypothalamic patterning. J Neurosci 29:6989-7002.
Willaredt MA, Hasenpusch-Theil K, Gardner HA, Kitanovic I, Hirschfeld-Warneken VC, Gojak CP, Gorgas K, Bradford CL, Spatz J, Wolfl S, Theil T, Tucker KL (2008) A crucial role for primary cilia in cortical morphogenesis. J Neurosci 28:12887-12900.
Friedrichs M, Larralde O, Skutella T, Theil T (2008) Lamination of the cerebral cortex is disturbed in Gli3 mutant mice. Dev Biol 318:203-214.
Theil T, Dominguez-Frutos E, Schimmang T (2008) Differential requirements for Fgf3 and Fgf8 during mouse forebrain development. Dev Dyn 237:3417-3423.
Zelarayan, L. C., Vendrell, V., Alvarez, Y., Dominguez-Frutos, E., Theil, T., Alonso, M. T., Maconochie, M. and Schimmang, T. (2007). Differential requirements for FGF3, FGF8 and FGF10 during inner ear development. Dev Biol 308, 379-91.
Theil, T. (2005). Gli3 is required for the specification and differentiation of preplate neurons. Dev Biol 286, 559-71.
Kuschel, S., Rüther, U. and Theil, T. (2003). A disrupted balance between Bmp/Wnt and Fgf signaling underlies the ventralisation of the Gli3 mutant telencephalon. Dev. Biol. 260, 484-495.
Alvarez, Y., Alonso, M. T., Vendrell, V., Zelarayan, L. C., Chamero, P., Theil, T., Bösl, M., Kato, S., Riethmacher, D. und Schimmang, T. (2003). Requirements for FGF3 and FGF10 during inner ear formation. Development 130, 6329-6338.
Hurtado-Vacalla, C. and Theil, T. (2002). Cst, a novel mouse gene related to Drosophila Castor, exhibits dynamic expression patterns during neurogenesis and heart development.Mech Dev., 118, 265-268.
Theil, T., Mc-Naughton, L. A., Manzanares, M ., Brodie, J. Krumlauf, R. and Wilkinson, D. G. (2002). Requirement for downregulation of kreisler during late patterning of the hindbrain. Development, 129, 1477-85.
Theil, T., Aydin, S., Koch, S. Grotewold, L. and Rüther, U. (2002). Wnt and Bmp signalling cooperatively regulate graded Emx2 expression in the dorsal telencephalon. Development, 129, 3045-54.