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A conserved transcription pathway in the involuting mammary gland

Reference	BB/D001315/1
Principal Investigator / Supervisor	Professor Richard Clarkson
Co-Investigators / Co-Supervisors	Professor Andrew Wyllie
Institution	Cardiff University
Department	School of Biosciences
Funding type	Research
Value (£)	232,847
Status	Completed
Type	Research Grant
Start date	01/03/2006
End date	31/10/2009
Duration	44 months

Abstract

We have identified a conserved family of transcription factors / here termed ces2-like proteins / that preliminary evidence suggests may play a role in the natural remodelling of mouse mammary gland following lactation. These genes are conserved in C. elegans where they encode one part of a transcription pathway that plays a role in regulating apoptosis during development. We believe that a similar transcription cascade may exist in mammals and that this pathway co-ordinates both apoptosis and remodelling processes in developing tissues. We aim to test this by studying in vivo and in vitro models of post-lactational mammary gland regression. We will characterise in detail the mammary phenotype of pre-existing knockout mouse lines for three of the four ces2-like genes. We will also complement this with a molecular analysis of mammary epithelial cells in culture in which these genes are overexpressed or inhibited (RNAi). Included in this molecular analysis will be the elucidation of the downstream transcriptional pathways, using microarray technology, and the relative involvement of known apoptosis regulators (eg. Stat3 and BH3-only proteins) and remodelling-associated genes (eg. vimentin, Snail and Slug). In this way we aim to establish for the first time a molecular link between the two established phases of mammary gland involution, that is, the transition from epithelial apoptosis to structural remodelling.

Summary

As animals grow and develop, their tissues reorganise themselves in a highly ordered way. The basic cellular processes required for this - motility, attachment, cell division and cell death - are shared in all multi-cellular organisms. Yet we know very little about the programmes that control these events, that is, which genes are involved and how they are regulated. The consequences of errors in these programmes can be severe, and may lead to major developmental defects, immune diseases or cancer. Two families of gene regulators that control embryonic development of the nematode worm, C. elegans, have also been found in mouse and man. Some individual members of these families have known functions in controlling cell death and cell attachments in mammals, but it is not yet clear whether they act together in the same way as they do in worms. We have preliminary evidence to suggest that these genes have a role in the reorganisation of mouse mammary gland tissue during a process known as involution. This occurs after the pups have weaned and involves the removal of the milk-producing cells of the gland which are no longer required. Our aim is to establish whether the same genetic pathway that controls worm development also controls the organisation of mouse mammary tissue. We will look at existing mice that carry mutations in these specific genes and we will establish how these mutations affect the structure and function of their mammary glands. To complement this work, and to minimise the number of animals required in this study, we will also model the effect of these genes in cultured cells. The consequences of this work are broad - providing important clues about how tissues are reorganised during development and demonstrating the existence of a biological process which has been highly conserved between worms and man.

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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