The role of Lin28a in thymic epithelial cell development and function

Kaya, Veysel. The role of Lin28a in thymic epithelial cell development and function. 2021, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: https://edoc.unibas.ch/84181/

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The thymus provides the stromal microenvironment crucial for the development of T cells. Thymic epithelial cells (TEC) constitute the most abundant cellular component of the thymic stroma and are indispensable for T cell generation, selection and maturation. TEC are classified into cortical (c) and medullary (m) epithelia based on their distinct anatomical locations, molecular phenotypes and functional features. MicroRNAs (miRNAs) are post- transcriptional regulators of gene expression that play crucial roles in numerous biological processes including cell fate determination, self-renewal, differentiation, proliferation and apoptosis. The importance of miRNA for TEC biology is reflected in the observation that miRNA-deficient TEC display defects in committing hematopoietic precursors to a T cell fate, mediating thymocyte positive selection and effecting normal promiscuous gene expression required for central tolerance induction. Lethal-7 (Let-7) miRNAs are the most abundant miRNAs in the genome, constitute a family of 10 conserved isomiRs encoded on different chromosomes and are critically involved in cell differentiation. Let-7 miRNAs are negatively regulated by the RNA binding proteins (RBPs) Lin28A and Lin28B. Both paralogues inhibit the generation of mature Let-7 transcripts and in addition regulate gene expression via direct mRNA target-binding, thus controlling multiple cellular processes such as development, cell- cycle control, differentiation, apoptosis and metabolism. However, the role of the Lin28/Let-7 axis is unknown for TEC development, function and maintenance. To investigate the importance of this axis, I expressed either Lin28A, Lin28B or both gene products in TEC using tissue-directed transgenesis. Lin28A and Lin28B differentially regulated thymic organ size, TEC maturation and function under the experimental condition doses. Thymic hypoplasia and hyperplasia were prominent findings in Lin28A and Lin28B transgenic mice, respectively. Their corresponding thymic size correlated with the number of early thymic progenitors (ETP) detected thus reflecting opposing roles for Lin28A and Lin28B. Both RBPs mediated changes in the mTEC subset composition whereas the cTEC compartment was only altered in Lin28A mutant animals. The changes in the composition of cTEC imposed by Lin28A impaired the positive and cortical negative selection of thymocytes. In adult mice, Lin28A mediated the persistence of phenotypically immature cTEC, that are more stringent in regulating thymocyte positive selection than cTEC with a mature phenotype. Finally, I show that Lin28A enhances glucose metabolism of cTEC and induces TEC apoptosis through tumor necrosis factor receptor 1 (TNF-R1) signaling. Taken together, this work demonstrates that Lin28A and Lin28B expression differentially affect both thymus development and function despite their comparable ability to target Let-7 transcripts thus identifying previously unrecognized roles for Lin28 in thymus biology.
Advisors:Holländer, Georg
Committee Members:Schär, Primo Leo and Anderson, Graham
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Pädiatrische Immunologie (Holländer)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Pädiatrische Immunologie (Holländer)
UniBasel Contributors:Holländer, Georg and Schär, Primo Leo
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14254
Thesis status:Complete
Number of Pages:129
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss142543
edoc DOI:
Last Modified:10 Sep 2021 04:30
Deposited On:09 Sep 2021 08:49

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