We are investigating the molecular mechanisms that control cortical patterning.
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 certain forms of epilepsy and mental retardation. 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 during embryonic development. Furthermore, cortical neurons have to make appropriate axonal contacts with neurons either within or outside the cortex to allow the establishment of a functional cortical circuitry. 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 the axonal connections between these neurons are established.
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). Such patients may suffer from mental retardation due to the absence of the corpus callosum, the major fiber tract connecting the two cerebral hemispheres. In our lab, we are characterizing cortical development in Gli3 mutant mice to identify the mechanisms which lead to mental retardation in GLI3 syndrome patients.
The cerebral cortex develops from the dorsal telencephalon. In an early phase of its development, the telencephalon becomes subdivided into different regions including the cortex. This regionalization process is governed by a number of signalling molecules. These are produced locally and form concentration gradients, thereby controlling the development of adjacent telencephalic cells. For example, the expression of Wnt genes in the dorsal midline of the telencephalon, the cortical hem, is required for the development of the hippocampus, an important cortical structure which is involved in memory and learning. In the Gli3 null mutant extra-toes (XtJ), the cortical hem fails to form and these Wnt genes are not expressed leading to the absence of the hippocampus. We are currently using a microarray screen comparing the expression patterns of genes in the wildtype and XtJ/XtJ telencephalon to identify genes which are regulated by Wnt genes in the developing hippocampus.
Once cortical neurons have been specified they have to make proper contact with their target cells. Prominent among these axonal connections of the cerebral cortex are the corpus callosum which connects the two cerebral hemispheres and the corticothalamic/thalamic tract which conveys information between the thalamus and the cortex. We are investigating the molecular mechanism which controls the formation of these fiber tracts and we are specifically interested in how early patterning defects in the telencephalon may lead to axon pathfinding defects in the cortex. To this end, we are using the Polydactyly Nagoya (Pdn) mouse mutant which carries a hypomorphic Gli3 mutation and Gli3 conditional knock-out mice. We could already show that, similar to Acrocallosal patients, Pdn mutants lack the corpus callosum and also have defects in the development of the corticothalamic/thalamocortical tract. We already showed how early regionalization defects present in these mutants can cause these axon pathfinding defects and we are currently investigating the genes regulated by Gli3 during patterning.
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.