Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.789234
Title: The role of the Hippo pathway in pituitary development and postnatal homeostasis
Author: Lodge, Emily Jane
ISNI:       0000 0004 8500 267X
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 pituitary is a primary endocrine organ that controls major physiological processes including growth, metabolism, the stress response and fertility; formed of hormone producing cells that arise from pituitary stem cells. Defects in the regulation of pituitary stem cells can affect hormone production or result in tumourigenesis. The Hippo pathway has been implicated in the control stem cell activity, however has not been previously studied in the pituitary. The Hippo pathway is a kinase phosphorylation cascade; active MST kinases activate LATS kinases, which phosphorylate and inactivate Hippo effectors YAP and TAZ. I have demonstrated via RNAscope mRNA in situ hybridisation and immunofluorescence that the Hippo pathway is expressed and active at developmental timepoints and in the postnatal gland. Effectors YAP and TAZ are specifically expressed in SOX2+ pituitary stem cells at postnatal time points, and we have used murine models including pituitary specific CRE driver (Hesx1Cre/+) to analyse knockout and overexpression models, including analysis of potential upstream factors DCHS1 and FAT4. I have identified a requirement for the control of YAP and TAZ both developmentally and postnatally; specifically, LATS kinases are required to control growth and differentiation, loss of both LATS1 and LATS2 (Hesx1Cre/+;Lats1fl/fl;Lats2fl/fl) leads to an undifferentiated overgrowth phenotype during development, which is not seen when MST kinases are lost. In addition, postnatal examination of pituitaries lacking LATS1 (Hesx1Cre/+;Lats1fl/fl) identified undifferentiated tumours, which arise from SOX2+ cells lacking LATS1 (Sox2CreERT2/+;Lats1fl/fl). Overexpression of YAP (Hesx1Cre/+;R26rtTA/+;Col1a1YAP-TetO/+) developmentally reduces differentiation but does not cause overgrowth. Postnatal YAP overexpression does not lead to tumours formation, however results in expansion of SOX2+ cells whilst DOX induction is ongoing, once DOX is removed SOX2 population reduces to normal levels. As increased levels of YAP increase pituitary stem cell activity, this could lead to new developments in regenerative medicine and our understanding of pituitary stem cells.
Supervisor: Andoniadou, Cynthia ; Tucker, Abigail Saffron Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.789234  DOI: Not available
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