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MUP knockout mice: implications for chemical communication and a generic research tool

Reference	BB/C503970/1
Principal Investigator / Supervisor	Professor Sir Martin Evans
Co-Investigators / Co-Supervisors	Dr Fiona Mansergh
Institution	Cardiff University
Department	School of Biosciences
Funding type	Research
Value (£)	292,558
Status	Completed
Type	Research Grant
Start date	01/04/2005
End date	31/08/2008
Duration	41 months

Abstract

The urine of the house mouse contains substantial quantities of lipocalin proteins termed Major Urinary Proteins (uMUPs) that are synthesised in the liver, and eliminated in urine. These proteins, expressed by both sexes (contrary to received wisdom), are products of a multigenic and highly polymorphic gene complex on chromosome 4. They bind, and slowly release volatile pheromones and act as information carrying molecules in their own right ¿ the uMUP profile constitutes a stable molecular signature that defines ownership of urinary chemosignals. We will construct transgenic mice (in Cardiff) in which uMUP genes are ablated, in order to create a null-uMUP mouse on two different, widely used lineages of laboratory rodents; 129 and C57BL/6. This will require deletion of approx. 1Mbp of DNA on chromosome 4, either using a single targeting vector with homology arms embracing the complete region, or a pair of targeting vectors that will flank the deletion with loxP sites, such that Cre-mediated recombination will eliminate the MUP region. Pathobiology of homozygous null-uMUP mice will be assessed at Cardiff. Null-MUP heterozygote mice of both strains will be transferred to Liverpool, where numbers will be expanded sufficiently for a range of behavioural and biochemical analyses that will determine the roles played by uMUPs in chemical communication, and assess any positive or negative consequences for animal welfare. These investigations will include same-sex aggression, mother:pup recognition, reproductive performance and growth rate. Inbred mouse strains provide a genetically homogenous background for these studies. More challenging tests of the role of uMUPs will ensue when the null uMUP phenotype is crossed into wild mice, over at least three generations. This will allow assessment of the outcome of uMUP ablation in the context of the full range of normal behaviours, a situation that does not occur in inbred strains. The mice will be used to assess the role of uMUPsin female recognition of male scents, male recognition of female scents, and in individual recognition and perception of ownership signals. Null-uMUP C57BL mice will be backcrossed against an MHC congenic on the same strain. This will allow us to resolve the interaction between MHC-mediated and MUP-mediated chemical signals in urine. It has not previously been possible to selectively manipulate these macromolecular components of an odour profile. In addition to providing a powerful tool to explore the semiochemistry, physiology and socio-biology of null-uMUP mice, the transgenic inbred strains have a much wider applicability in biomedical research. Disruption of male pheromone output may have dramatic effects on inter-male aggression, and could lead to strategies for enhanced welfare of laboratory rodents.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Animal Welfare, The 3 Rs (Replacement, Reduction and Refinement of animals in research)
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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