Analysis of cell proliferation during C.elegans intestine development

Segref, Alexandra (2007) Analysis of cell proliferation during C.elegans intestine development. PhD thesis, University of Glasgow.

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The precise co-ordination of cell proliferation and developmental pathways is essential for the development of multicellular organisms and the maintenance of tissue homeostasis. The intestine (endoderm) of the nematode Caenorhabditis elegans is used as a model system to study the control of cell proliferation during development, because it consists of only 20 cells. These cells are generated in the embryo by a precise division-pattern that is largely invariant between different animals. Previously, a cdc-25.1 (ij48) gain-of-function allele has been identified that produces increased numbers of intestinal cells. CDC-25.1 belongs to the eukaryotic CDC25 family of positive-acting cell cycle regulators. Intriguingly, in cdc-25.1 (ij48) mutants, proliferation of other tissues is unaffected, but knockdown of CDC-25.1 by RNAi produces reduced cell divisions in most lineages. Thus, there is a general requirement for cdc-25.1 function in all embryonic blastomeres, but the cdc-25.1(ij48) mutant primarily affects proliferation of the intestine. It is therefore interesting to elucidate the mechanism underlying this tissue-specific phenotype. The ij48 lesion in CDC-25.1 constitutes a serine to phenylalanine mutation (CDC- 25.1(S46F)) in a highly conserved putative DSG consensus site, which may act as a site of negative regulation of CDC-25.1. In mammalian cells, the DSG motif of CDC25A acts as a recruitment site for the ubiquitin ligase component beta-TrCP, mediating ubiquitin-dependent degradation of CDC25A. However, to date no difference in the abundance or localisation of CDC-25.1(S46F) was identified. In this thesis, I set out to identify negative regulators of CDC-25.1 that control CDC-25.1 through S46, possibly in the intestine. Compelling evidence is provided demonstrating that LIN-23, the C. elegans orthologue of human beta-TrCP, negatively regulates the abundance of CDC-25.1 through S46 in C. elegans, specifically in early embryos. Surprisingly, the control of CDC-25.1 abundance is not restricted to intestinal cells, suggesting that the intestinal cell proliferation is more sensitive to elevated CDC-25.1 protein levels than other cell types. In a search for other molecules that may regulate the DSG site, GSK-3, APR-1 and WRM-1 were found to also cause excess intestinal cells. Intriguingly, their function is independent of S46 in CDC-25.1, because gsk-3, apr-1 or wrm-1 RNAi produce a synergistic increase in intestinal cells when combined with the cdc-25.1(ij48) allele. Thus, this thesis provides new insights to further our understanding of how the multicellular organism C. elegans controls proliferation of an entire tissue, the intestine.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: L L Johnstone
Keywords: Developmental biology
Date of Award: 2007
Depositing User: Enlighten Team
Unique ID: glathesis:2007-74000
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2019 15:33
Last Modified: 23 Sep 2019 15:33

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