Role of Gli3 in thalamocortical tract development

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Integrative Physiology

Abstract

Our research deals with the development of the cerebral cortex which 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. During embryonic development the nerve cells which constitute the cortex have to form the appropriate connections with nerve cells either within or outside of the cerebral cortex enabling the cerebral cortex to communicate with other regions of the brain. In general, our research aims at identifying the fundamental mechanisms that allow neurons to make these connections. We are particularly interested in the role of the GLI3 gene which is mutated in a number of human syndromes. Such patients often suffer from mental retardation. We want to investigate the role of the Gli3 gene in the formation of appropriate connections between cortical nerve cells and their target cells in the thalamus. From this analysis, we expect further clues to our understanding of the causes underlying mental retardation in human patients.

Technical Summary

The cerebral cortex is responsible for all higher cognitive functions unique to humans. Its malfunction underlies a number of neural disorders including epilepsy, autism and mental retardation (MR) which often manifest as malformations during embryonic development. An important aspect of cortical development is the formation of correct axonal connections of its neurons with their target cells. Indeed, axon pathfinding defects in the cerebral cortex are one of the major causes of mental retardation.
Our labs are interested in the function of the Gli3 zinc finger transcription factor during cortical development. Mental retardation is a component in 2 out of 5 human syndromes in which mutations in the human GLI3 gene have been identified. Acrocallosal syndrome represents a specific form of MR which is characterized by the absence of the corpus callosum, the major fiber tract connecting the left and right cerebral hemisphere. Also, a subset of Greig cephalopolydactyly syndrome patients are mentally retarded but these patients show normal callosal development suggesting that other cortical defects underlie the disease.
In this proposal, we want to use the Gli3 mutant mouse Pdn as a model to investigate axon pathfinding defects in the forebrain of these animals and by interference in ACS/GCPS patients. We will study axon guidance at the thalamocortical/corticothalamic tract (TCT) which conveys sensory and motor information between the thalamus and the cortex. Defects in this tract may contribute to the severity in GLI3 syndrome patients. Our analysis has already shown that Pdn mutant embryos show axon pathfinding defects of the TCT. We will now test several hypotheses concerning the mechanisms underlying these defects using a combination of marker analysis and tissue transplantation experiments. By this approach, we will investigate the development of corticothalamic neurons and their axonal projections and the development of the thalamus in the Pdn mutant mouse. We will also investigate the role of the ventral telencephalon in guiding corticothalamic and thalamocortical axons to their respective target areas. From this analysis, we expect important insights into the mechanisms underlying TCT formation and thereby further elucidating possible causes leading to MR.

Publications

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Magnani D (2010) The Gli3 hypomorphic mutation Pdn causes selective impairment in the growth, patterning, and axon guidance capability of the lateral ganglionic eminence. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Magnani D (2013) Gli3 controls subplate formation and growth of cortical axons. in Cerebral cortex (New York, N.Y. : 1991)

 
Title vibratome 
Description We purchased a vibratome which enabled us to do transplantation experiments which we were not able to do before. This vibratome is also used by other groups in the Centre for Integrative Physiology helping their research. 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact This vibratome helped to develop a transplantation assay which we were not able to do before significantly increasing the quality of our research. This method was subsequently used by members of the David Price and Tom Pratt lab at the Centre for Integrative Physiology. 
 
Description Gli3 controls corticothalamic pathfinding by regulating development of the piriform cortex 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Theil lab: planning experiments, performing experiments, writing the manuscript
Collaborator Contribution John Mason: planning experiments, contributed to writing the manuscript
Impact Amaniti, E. M., Fu, C., Lewis, S., Saisani, M., Magnani, D., Mason, J. O. and Theil, T. (2015). Gli3 controls corticothalamic pathfinding by regulating development of the piriform cortex. Cerebral Cortex 25, 460-71.
Start Year 2011
 
Description Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of pRb. 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution My lab helped with the DNA binding assays and the reporter gene assays in the paper and we contributed to writing the manuscript.
Collaborator Contribution Planning and execution of most of the experiments. Writing the manuscript
Impact This collaboration has resulted in a paper (PMID: 23622063) and has prompted us to start to analyse a role of the cell cycle in the Gli3 mutants we are working on.
Start Year 2011
 
Description Role of Dmrt5 in telencephalic development 
Organisation Free University of Brussels
Department Institute of Molecular Biology and Medicine (IBMM)
Country Belgium, Kingdom of 
Sector Academic/University 
PI Contribution We provided Gli3 mouse mutants to analyze whether Gli3 lies upstream of Dmrt5; We analyzed whether Dmrt5 is regulated by Wnt signalling using an in vitro culture assay
Collaborator Contribution Our partners characterized development of the telencephalon in Dmrt5 mutant mice.
Impact 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
Start Year 2011
 
Description Role of corticothalamic axons in guiding thalamocortical axons 
Organisation University of Edinburgh
Department Centre for Integrative Physiology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We performed a transplantation assay which directly tested the role corticothalamic axons in guiding thalamocortical axons into the cortex
Collaborator Contribution Our partners characterized the development of the thalamocortical/corticothalamic tracts in an APC mouse mutant.
Impact 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.
Start Year 2011
 
Description Role of primary cilia in the development of the corpus callosum 
Organisation Claude Bernard University Lyon 1 (UCBL)
Department Center for Molecular and Cellular Genetics and Physiology
Country France, French Republic 
Sector Academic/University 
PI Contribution We analyzed early patterning in Rfx3 mutant mice in which defective cilia formation leads to agenesis of the corpus callosum
Collaborator Contribution Our partners characterized the formation of the corpus callosum in Rf3 mutants.
Impact 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
Start Year 2010
 
Description The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating patterning of prethalamus and ventral telencephalon 
Organisation Claude Bernard University Lyon 1 (UCBL)
Country France, French Republic 
Sector Academic/University 
PI Contribution We have made the vast majority of the analysis and wrote the manuscript.
Collaborator Contribution Benedicte Durand at the University of Lyon 1 provided the Rfx3 mutant mice, made some quantification experiments and contributed to writing the manuscript. Stephane Schurmans provided the Inpp5e mutant mice.
Impact 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
Start Year 2011
 
Description The ciliogenic transcription factor Rfx3 is required for the formation of the thalamocortical tract by regulating patterning of prethalamus and ventral telencephalon 
Organisation University of Liege
Department Interdisciplinary Cluster for Applied Genoproteomics (GIGA)
Country Belgium, Kingdom of 
Sector Academic/University 
PI Contribution We have made the vast majority of the analysis and wrote the manuscript.
Collaborator Contribution Benedicte Durand at the University of Lyon 1 provided the Rfx3 mutant mice, made some quantification experiments and contributed to writing the manuscript. Stephane Schurmans provided the Inpp5e mutant mice.
Impact 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
Start Year 2011