Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.789306
Title: The role of WNT signalling in the developing and postnatal pituitary gland
Author: Russell, John Parkin
ISNI:       0000 0004 8500 6064
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Abstract:
The mouse pituitary is a primary endocrine organ that undergoes a phase of rapid growth during the postnatal stages of life, when populations of hormone-secreting cell types expand to meet physiological demand. The regulation of these populations is critical for optimal organ function; failure can lead to pituitary disorders such as hypopituitarism or pituitary tumours. SOX2+ pituitary cells are thought to be archetypical stem cells: they are capable of self-renewal in vitro and are multipotent in vivo, containing the potential to differentiate in to all hormone lineages. However, the activity of this population drastically declines over the course of the post-natal period. Using a combination of genetic tools (Sox2CreERT2/+;R26mTmG/+ and Sox2CreERT2/+;R26Confetti/+ mouse lines), I sought to characterise the changing dynamics of this population. My work has established that Sox2 cells have self-renewal capacity in vivo and contribute to the generation of endocrine cell types during the postnatal growth phase. Global gene expression profiling of Sox2 cells during these stages revealed the activation of several signalling pathways likely involved in their regulation. A key pathway influencing proliferation and cell fate commitment in many tissues is the WNT signalling cascade. I identified that cells of the anterior pituitary respond robustly to WNT signals at early postnatal stages, however the majority of this response occurs outside of the Sox2 cells, which are mostly resistant to activation. In vitro isolation of WNT-responsive Sox2 cells reveals they have a high potential to proliferate and form colonies in vitro, suggesting an activating role for WNT signalling in a minority of the stem cells. Using a combination of genetic tools to manipulate components of the WNT pathway I confirm a role in promoting proliferation of lineage committed cells. My data reveal that despite their resistance, Sox2 cells are capable of responding to WNT signals and in fact, are enriched for components of this pathway including LGR/R-SPONDIN signalling, WNT inhibitors ZNRF3/RNF43 and downstream WNT targets, suggesting these are poised for activation. Through mis-expression of R-SPONDIN 1 in the pituitary, I demonstrate that the stem cell potential of Sox2 cells can be activated by enhancing their WNT response. Lineage tracing of WNT-responsive cells using an Axin2CreERT2/+ mouse line revealed that these more committed cells provide the bulk of growth and generation of endocrine cell types across all lineages and have a greater proliferative potential than Sox2 cells during homeostasis. My data reveal that Sox2 cells themselves can act as a source of WNT ligands, providing a niche for their own progeny. These findings are of relevance to regenerative medicine approaches and the better understanding of possible causes of pituitary disorders. My thesis elucidates the dynamics between these two distinct populations, identifies the differential role WNT signalling in each as well as the influence of this signalling pathway in the generation of endocrine cells.
Supervisor: Andoniadou, Cynthia ; Tucker, Abigail Saffron Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.789306  DOI: Not available
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