Dr Thomas Theil

Personal profile

• 2015: Reader, University of Edinburgh
• 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

Research Theme

• Genes and Development

Research

Dr Thomas Theil's research briefing

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 that control the activity of cortical stem cell, their proliferation and neuronal differentiation leading to the generation of different types of cortical neurons in appropriate numbers. We are particularly interested in how cell signalling and transcriptional regulation converge to control cortical neuron formation.

Gli3 zinc finger transcription factor

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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 macrocephaly and intellectual disability. In our lab, we are characterizing cortical development in Gli3 mutant mice to identify the mechanisms that 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, Gli3 controls the onset of cortical neurogenesis that is delayed in Gli3 conditional mutants by regulating the expression of the cell cycle gene Cdk6. These findings have implications for the macrocephaly observed in GCPS patients.

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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. Inpp5e mutant mice show an increase in direct neurogenesis at the expense of indirect neuron formation due to reduced Gli3 repressor formation. Thus, elucidating the mechanisms and signals that primary cilia use to control cortical stem cell

development helps 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.

We are also using human cortical organoid models to study ciliary function in human corticogenesis. Interestingly, loss of INPP5E function leads to the formation of ventral telencephalic neurons. This findings implicate cilia in human dorsal/ventral patterning of the telencephalon and shed new lights how distinct pallial and subpallial domains are established in human cortex.

Finally, several ciliary genes are mutated in autism spectrum disorder (ASD) and several cilia controlled signalling pathways have been implicated in the aetiology of ASD. Therefore, we started studying the effects of ASD mutations in the ciliary gene CEP41 on cortical stem cells in a human organoid model. This study will have implications for our understanding of the hitherto poorly characterised role of cilia in the pathology of ASD

Funding

• Simons Initiative for the Developing Brain (SIDB)

Team members

• Kerstin Hasenpusch-Theil (Postdoctoral Researcher)
• Zewen Ding (PhD student)

Collaborations

• Prof David Price (University of Edinburgh)
• Prof John Mason (University of Edinburgh)
• Dr Tom Pratt (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)

Publications

Schembs,L., Willems,A., Hasenpusch-Theil, K., Cooper, J.D., Whiting, K., Burr, K., Bøstrand, S.M.K., Selvaraj, B.T., Chandran, S., Theil, T.(2022). The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic Hedgehog signalling. Cell Rep. 39:110811. doi: 10.1016/j.celrep.2022.110811.

Hasenpusch-Theil, K., and Theil, T. (2021). The Multifaceted Roles of Primary Cilia in the Development of the Cerebral Cortex. Front Cell Dev Biol 9: 630161.

Hasenpusch-Theil, K., Laclef, C., Colligan, M., Fitzgerald, E., Howe, K., Carroll, E., Abrams, S. R., Reiter, J. F., Schneider-Maunoury, S. and Theil, T. (2020). A transient role of the ciliary gene Inpp5e in controlling direct versus indirect neurogenesis in cortical development. Elife 9:e58162. doi: 10.7554.

Bas-Orth, C., Schneider, J., Lewen, A., McQueen, J., Hasenpusch-Theil, K., Theil, T., Hardingham, G. E., Bading, H. and Kann, O. (2020). The mitochondrial calcium uniporter is crucial for the generation of fast cortical network rhythms. J Cereb Blood Flow Metab 40, 2225-2239.

Ratié L., Desmaris E., García-Moreno F., Hoerder-Suabedissen A., Kelman A., Theil T., Bellefroid E.J., Molnár Z. (2020). Loss of Dmrt5 Affects the Formation of the Subplate and Early Corticogenesis. Cerebral Cortex. 30, 3296-3312.

6) Hasenpusch-Theil, K., West, S., Kelman, A., Kozic, Z., Horrocks, S., McMahon, A. P., Price, D. J., Mason, J. O. and Theil, T. (2018). Gli3 controls the onset of cortical neurogenesis by regulating the radial glial cell cycle through Cdk6 expression. Development 145, dev163147

Ruiz-Reig, N., Andres, B., Lamonerie, T., Theil, T., Fairen, A. and Studer, M. (2018). The caudo-ventral pallium is a novel pallial domain expressing Gdf10 and generating Ebf3-positive neurons of the medial amygdala. Brain Struct Funct 223, 3279-3295.

E. Desmaris, M. Keruzore, A. Saulnier, L. Ratie, S. Assimacopoulos, S. De Clercq, X. Nan, K. Roychoudhury, S. Qin, S. Kricha, C. Chevalier, T. Lingner, K. A. Henningfeld, D. Zarkower, A. Mallamaci, T. Theil, K. Campbell, T. Pieler, M. Li, E. A. Grove and E. J. Bellefroid. (2018). DMRT5, DMRT3, and EMX2 Cooperatively Repress Gsx2 at the Pallium-Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors. J Neurosci, 38, 9105-9121.

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.

Thomas Theil publication list (PDF)

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