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dc.contributor.advisorBlackburn, Clareen
dc.contributor.advisorLowell, Sallyen
dc.contributor.authorLiu, Dongen
dc.date.accessioned2018-07-24T09:23:25Z
dc.date.available2018-07-24T09:23:25Z
dc.date.issued2018-07-09
dc.identifier.urihttp://hdl.handle.net/1842/31405
dc.description.abstractThymic epithelial cells (TECs) are indispensable for the development of T cells in the thymus. Two subtypes of TECs exist in the thymus, medullary mTECs and cortical cTECs. Both mTECs and cTECs originate from endodermal thymic epithelial progenitor cells (TEPCs) in the embryo, but how the differentiation of TEPCs is regulated is not well understood. The aims of this thesis were to establish the role of Notch signalling in TEPC differentiation, and how it interacts with known regulators such as FOXN1 and the NFκB pathway. Gene expression data showed that Notch is active in TEPCs and exhibits a correlation with the mTEC lineage. Loss of Notch function led to a significant reduction in the number of mTECs in the thymus, and this can be attributed to aberrant mTEC specification. Furthermore, the duration of Notch activity in determining mTEC number appears limited to the early phase of organogenesis, and precedes RANK/NFκB mediated mTEC proliferation. Gain of Notch function resulted in a considerable shift to a primitive, TEPC-like phenotype, and subsequently a latent increase in mTEC frequency. Finally, transcriptomic and functional analyses pointed to a cross-repressive mechanism between Notch and FOXN1 in TEPCs. Taken together, these results identified Notch as a novel regulator of mTEC specification, likely through maintaining the potency of fetal TEPCs, a prerequisite for mTEC lineage commitment.en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionBredenkamp, N., Jin, X., Liu, D., O'Neill, K. E., Manley, N. R. and Blackburn, C. C. (2015). Construction of a functional thymic microenvironment from pluripotent stem cells for the induction of central tolerance. Regen Med 10, 317-329.en
dc.subjectthymic epithelial cellsen
dc.subjectTECsen
dc.subjectcTECsen
dc.subjectmTECsen
dc.subjectNotch pathwayen
dc.subjectNotch signallingen
dc.titleTowards understanding the signalling requirements of thymic epithelial progenitor cellsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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