Award details

A mouse model for studying talpid3 and its role in hedgehog signalling

Reference	BB/E014496/1
Principal Investigator / Supervisor	Professor Emeritus Cheryll Tickle
Co-Investigators / Co-Supervisors
Institution	University of Bath
Department	Biology and Biochemistry
Funding type	Research
Value (£)	252,080
Status	Completed
Type	Research Grant
Start date	01/10/2007
End date	30/09/2010
Duration	36 months

Abstract

We have identified a new gene required for the response to hedgehog signalling in vertebrates in collaboration with Dave Burt at the Roslin Institute. This advance came through studying the chicken mutant, talpid3, and is the first example of a successful positional cloning exercise in chickens. talpid3is a recessive embryonically lethal mutation and leads to multiple defects in regions of the embryo that depend on hedgehog signalling including limb, face, nervous system. Since hedgehog signalling is involved in so many cell-cell interactions in vertebrate embryos and implicated in an increasing number of human tumours, understanding the precise role of the talpid3 gene product has wide implications. The talpid3 protein is completely novel and has not previously been attributed any function. There are mouse and human orthologs but no related genes in Drosophila. In order to test the function of talpid3 genetically we will make a conditional mouse line and generate talpid3 knock-out mouse embryos. We will also carry out epistasis experiments by generating double mutant mouse embryos deficient both in talpid3 and in genes encoding other components of the hedgehog pathway. This will test interactions between talpid3 and the products of other hedgehog pathway genes and shed light on the precise role of talpid3. The conditional mouse line will also generate a resource that can be used to knock out talpid3 in specific parts of the embryo. In this project we will focus on generating conditional knock-outs in the limb to explore the role of talpid3 in patterning and in later developmental events such as ossification. This project will also be the first time that the consequences of lack of function of the same gene has been studied in chicken and mouse embryos and this provide fascinating insights into how differences in anatomy arise during embryonic development.

Summary

One of the biggest challenges in biology is to understand how a single cell, the fertilised egg, gives rise to organised arrays of cells and tissues and how all the different parts of the body develop in the right places. Recently we have discovered a new gene that is essential for proper development of the embryo. This stemmed from studying an inherited condition in chickens in which the embryos have many defects and die before development is complete. Further work in chick embryos revealed that this gene is required for responding to a cell-cell signalling molecule that controls the development of many parts of the embryo including the limb, brain and face. The cell-cell signalling molecule has also been associated with tumours. Now we have identified the gene responsible for producing the embryonic defects in the mutant chicken embryos, we wish to understand how the protein it encodes works. There are related human and mouse genes. In this project we wish to make mouse models in which we inactivate the related gene either in all the cells of the embryo or specifically in the developing limb. We will also generate embryos that are deficient both in this gene and also other genes in the hedgehog pathway so that we can work out how the genes interact. This will provide one route to exploring the function of the gene and the protein it encodes. Embryos from the mouse models can be frozen down and thus also create a long term resource for studying a crucial cell-cell signalling pathway in development.

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	X – not assigned to a current Research Topic
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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