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The role of Gli3 in development of the telencephalon

Reference	BB/D002311/1
Principal Investigator / Supervisor	Professor John Mason
Co-Investigators / Co-Supervisors	Dr Vassiliki Fotaki, Professor David Price, Dr John West
Institution	University of Edinburgh
Department	Biomedical Sciences
Funding type	Research
Value (£)	464,863
Status	Completed
Type	Research Grant
Start date	01/11/2005
End date	31/10/2008
Duration	36 months

Abstract

Mice harbouring null mutations in the gene encoding the transcription factor Gli3 (extra toes mice, XtJ) exhibit a variety of severe abnormalities in the embryonic forebrain, indicating that Gli3 is essential for the normal development of this tissue. However, its detailed mechanism of action is not yet understood. We propose to use three complementary approaches to elucidate the important regulatory role played by Gli3 during development of the telencephalon.(i) We and others have found that the expression of signalling molecules in a signalling centre located in the dorsalmost part of the developing telencephalon is lost in XtJ/XtJ mutants. This raises the possibility that the loss of these molecules may contribute to the telencephalic phenotype of the mutant. We will generate a set of Gli3-/-:Gli3+/+ chimaeric embryos to determine whether the actions of Gli3 are cell-autonomous, cell non-autonomous or a mixture, and whether these actions differ in various regions of the telencephalon. (ii) We will also generate a set of conditional mutations of Gli3 using the cre-loxP system to specifically inactivate Gli3 in a set of defined domains within the developing telencephalon. Detailed characterisation of these mutants at the molecular and histological level will allow us to determine how Gli3 contributes to dorsoventral patterning of the telencephalon. (iii) We will systematically examine cell proliferation, differentiation and death in the telencephalon of XtJ/XtJ embryos from E8.0, the time at which Gli3 expression is first seen. We will also examine the telencephalon of Shh-/- mutants to examine the complex interplay between Shh and Gli3 in this tissue. The combination of these three approaches gives us a powerful way to unravel the precise role(s) of Gli3 in telencephalic development.

Summary

The mammalian brain is one of the most complex biological structures known. During embryonic development, the brain is formed from a small region at the front end of the embryo. This region grows rapidly as cells within it divide. Ultimately, it gives rise to each part of the adult brain - the cortex, cerebellum, hippocampus and so on. Newborn cells arising in the embryonic brain must be given instructions to tell them which part of the brain they should become part of. These instructions are encoded by genes within the cells. One way that we can better understand exactly how such genes instruct cells to build a brain is by studying mice that have a mutation in a gene that affects development of the brain. In such mice, the brain does not form properly and by working out what has gone wrong, we can often more clearly understand the type of instruction that the gene would normally give. Our project is aimed at understanding how one such gene, named Gli3, instructs cells to become part of the forebrain - an important part of the brain needed for thought. Two of the main ways in which genes can instruct cells are (i) by acting within the cell itself to tell it what to do or (ii) by making the cell produce a factor that then tells neighbouring cells what to do. We can use sophisticated genetic techniques to discover which of these two methods Gli3 normally uses. We can make embryos which are a mixture of Gli3 mutant cells and normal cells. In such embryos, if Gli3 acts within the cells themselves to tell them what to do, then the Gli3 mutant cells in the mixed embryo will not be normal, because they lack Gli3. If, however, Gli3 normally acts by instructing cells to make factors that tell neighbouring cells what to do, then the normal cells in the mixed embryo (which have normal Gli3) will still make the factors, so the Gli3 mutant cells will behave as if they were normal, because they receive the factor made by the normal cells around them. Similarly, we can make mutantmice which have mutant copies of Gli3 in some parts of the brain, but normal Gli3 in all of the rest of the embryo. By looking carefully at these embryos we can work out whether mutations in Gli3 only affect cells that have the mutation, or whether nearby normal cells are affected too. In this way, we can find out about the type of instructions that Gli3 normally gives and make important discoveries about the mechanisms that control the normal development of the brain.

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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