dc.contributor.advisor | Blackburn, Clare | en |
dc.contributor.advisor | Lowell, Sally | en |
dc.contributor.author | Liu, Dong | en |
dc.date.accessioned | 2018-07-24T09:23:25Z | |
dc.date.available | 2018-07-24T09:23:25Z | |
dc.date.issued | 2018-07-09 | |
dc.identifier.uri | http://hdl.handle.net/1842/31405 | |
dc.description.abstract | Thymic 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.iso | en | |
dc.publisher | The University of Edinburgh | en |
dc.relation.hasversion | Bredenkamp, 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.subject | thymic epithelial cells | en |
dc.subject | TECs | en |
dc.subject | cTECs | en |
dc.subject | mTECs | en |
dc.subject | Notch pathway | en |
dc.subject | Notch signalling | en |
dc.title | Towards understanding the signalling requirements of thymic epithelial progenitor cells | en |
dc.type | Thesis or Dissertation | en |
dc.type.qualificationlevel | Doctoral | en |
dc.type.qualificationname | PhD Doctor of Philosophy | en |