Bosch, Angela Jeanne Tamara. The role of the transcription factor Foxn1 in Thymus organogenesis and maintenance. 2014, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10964
In the context of thymus organogenesis, Foxn1 serves as a master transcription factor essential for TEC development. The loss of Foxn1 constitutes then a molecular cause for athymia as the molecules absence blocks TEC growth and differentiation. Consequently the epithelial cells adapt another cell fate and the thymus rudiment fails to attract lymphoid precursors.
Mice with either a reduced or time restricted Foxn1 expression at the onset of thymus organogenesis displayed a severely disturbed thymus development. Though able to develop into cTEC and mTEC, they remain in an immature state as demonstrated by the absence of mature TEC. Similar as in congenital athymic nude mice, devoid of Foxn1 expression, also common bipotent progenitor TEC were detected. T-cell development was impaired resulting consequently in severe peripheral lymphopenia, which only slightly mitigated with progressive age. Importantly the peripheral T-cells in both mouse models differ from that of nude mice, in that cells with effector and regulatory functions were detected. Furthermore inadequate Foxn1 expression lead to colitis and early death. Bowel inflammation was associated with an increase in Th1 polarised CD4+ T-cells among intraepithelial and lamina propria lymphocytes.
In aggregate this study showed that TEC differentiation and maintenance depends on both a continuous and adequate Foxn1 expression, as short-term or low level Foxn1 expression were insufficient to sustain regular thymus development and function. Inadequate expression of Foxn1 expression resulted consequently in the loss/absence of a regular thymus microenvironment and selection of an autoreactive T-cell repertoire causing auto-immune colitis.
|Advisors:||Holländer, Georg A.|
|Committee Members:||Rolink, Antonius G. and Spagnoli, Giulio C.|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Pediatric Immunology (Holländer)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||145 Bl.|
|Last Modified:||30 Jun 2016 10:56|
|Deposited On:||30 Oct 2014 11:35|
Repository Staff Only: item control page