Muter, Joanne (2015) Uncoupling of circadian and other maternal cues in decidualizing endometrial cells. PhD thesis, University of Warwick.

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Abstract

The differentiation of human endometrial stromal cells (HESCs) into specialised decidual cells prepares the endometrium for embryonic implantation. The biochemical and morphological transformation of these cells is highly temporally regulated in order to define a transient period of endometrial receptivity. Currently, the involvement of circadian machinery, and clock dependent pathways in this process are not fully understood. Firstly, analysis of circadian rhythms in HESCs revealed a consistent loss of oscillations in clock components upon decidualization. Down-regulation of Period 2 (PER2) expression, apparent in the early stages of differentiation, was shown to be sufficient to cause this aperiodicity. In turn, temporal suppression of PER2 expression was achieved via reduced CLOCK binding to a non-canonical Ebox enhancer in the PER2 promoter. RNA sequencing analysis upon premature PER2 knockdown revealed a disorganised decidual phenotype in which cell cycle and mitotic regulators were perturbed. As such, PER2 acts to uncouple the endometrium from circadian oscillations during decidualization.

Secondly, the gene PRIP-1 was shown to be PER2 dependent in undifferentiated HESCs. Endometrial expression of PRIP-1 was induced and maintained upon decidualization by the post-ovulatory rise in progesterone. Analysis of Ca2+ fluxes demonstrated the ability of PRIP-1 to act as a chelator of IP3 signalling. Additionally, PRIP-1, via its regulation of the AKT pathway, is shown to be an anti-apoptotic regulator in decidual HESCs. Together, these results indicate PRIP-1 functions as a molecular switch in response to progesterone signalling. High PRIP-1 levels during differentiation enable AKT and IP3 mediated cell survival, whilst declining levels upon P4 withdrawal leads to decidual apoptosis.

In summary, I provide a novel paradigm whereby both PER2 and PRIP-1 act to uncouple the endometrium from various signalling inputs, enabling an autonomous decidual response. Asynchrony in these pathways can lead to a cascade of events resulting in an array of adverse pregnancy complications.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QM Human anatomy R Medicine > RJ Pediatrics
Library of Congress Subject Headings (LCSH):	Circadian rhythms, Endometrium, Miscarriage
Official Date:	November 2015
Dates:	Date Event November 2015 Submitted
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Brosens, Jan
Extent:	vi, 249 leaves : illustrations (colour), charts
Language:	eng

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