Role of Gli3 in thalamocortical tract development

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.

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.