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Pheromone signalling in mice

Reference	BB/D01526X/1
Principal Investigator / Supervisor	Professor Eric Keverne
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Zoology
Funding type	Research
Value (£)	398,128
Status	Completed
Type	Research Grant
Start date	12/06/2006
End date	11/08/2009
Duration	38 months

Abstract

Our establishment of VNO stem cell cultures have enabled us to study in detail the signalling mechanisms which both sustain and proliferate these developing neurones. We have also established the MUP lipocalin ligands as integral to this developmental regenerative process. This matches to the biology since VNO access to these non-volatile ligands occurs via oral and genital nuzzling. The aims and objectives of this project are:- 1) Establish co-cultures of VNO stem cells with target neurons in tissue slices from the accessory olfactory bulb in order to address questions of axonal outgrowth and the interactive mechanisms between VNO and AOB for axonal targetting of AOB. 2) Address the importance of receptor signalling for this process. V2Rs are linked via Galpha-o to activate phospholipase cb-2 to generate DAG and IP3 which link to TRPc2 channels for calcium entry. We will investigate the importance of activity dependent signalling through this pathway for axonal growth and targetting. We have access to the TRPc2 mutant for this study. 3) Since the MUP proteins have the capacity to sustain and proliferate the stem cell population of VNO receptor neurons and the same MUP ligands also participate in pheromone signalling, we will investigate the epigenetic effects of signalling on the regenerative process and how this influences life history changes in pheromone receptors according to need.

Summary

The human brain is both vast in size and complexity and in order to understand how it develops and responds to the environment it is necessary to model parts of its abilities based on simpler systems. In this study we are going to investigate pheromone communication (special chemicals which influence behaviour and reproduction) and we intend to use mice because they are particularly adept at responding to pheromones. We already know a great deal about the effects of pheromones at a functional level and this is an important starting point for developing insights in the molecules, cellular and genetic mechanisms that enable this functioning. Thus, the sensory priorities of mice change with ageing from being mother oriented to being sexually oriented. A question to be addressed, therefore, is do pheromone receptor neurons themselves change in the life history of the mouse, and if so how is this regulated The very nature of responding to chemical messages from the outside world inevitably exposes these neurones to toxins, temperature and humidity fluctuations which means they only live for a few weeks and need to be replaced. This implies there is something very special about these neurons that allows them to regenerate when injured and this might have future repercussions for understanding the repair of brain injury. The main questions we will address are:- What are the biological signals that trigger these neurons to regenerate, and what are the signals to which their extending projections (axons) respond in order to ensure they reach their appropriate target in the brain. This is not an easy question to answer since it requires stem cell neurons to be grown in culture and target neurons to be co-cultured in slices. We know that pheromones in urine and saliva act on these neurons and we know that without this kind of activity the neurones do not regenerate. Thus a second part of this investigation is to examine the regenerative power of these pheromones and howthey instruct the stem cells to regenerate.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Neuroscience and Behaviour, Stem Cells
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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