Transcription factor and growth factor requirements for thymus vascularization
Bryson, Jerrod Lamont
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Scientists and philosophers have marveled over the complex nature of the vascular system for many centuries. In this dissertation work, we were interested in unraveling the molecular mechanisms driving the structuring and organization of this elaborate network in the thymus. Specifically, our aim was to elucidate the possible contributions of a number of thymus-specific transcription factors and growth factors to vascular network formation. The thymus is a specialized microenvironment responsible for the development of self-tolerant and self-restricted T cells. In this dissertation, we used an allelic series of the thymic epithelial cell (TEC)-specific transcription factor Foxn1 to define normal thymic vascular development and to investigate a potential role for Foxn1-dependent TEC differentiation in the formation of the thymic vasculature. We show that endothelial cells initially enter the wild-type thymus at E13.5, with PDGFR-β+ mesenchymal cells following at E14.5. These events are delayed by 1-2 days in Foxn1∆/∆ mice, and were accompanied by an apparent loss of capillaries. In Foxn1∆/nu mice, endothelial cells could not be detected in the thymus until E15.5, and never enter in Foxn1nu/nu null mutants. VEGF-A and PDGF-B expression are reduced at E13.5 and E15.5 in Foxn1∆/∆ mice compared with controls. Further, empty collagen IV sleeves (collagen IV+ CD31-) were present throughout the mutant thymus. Additionally, we tested the requirement for TEC-derived Shh, VEGF-A, and BMP4 for thymus vascularization. Deletion of these genes in TECs using Foxn1Cre resulted in no observable delay in initial thymus vascularization suggesting that they may be dispensable for thymus vascularization. Together, these data suggest that Foxn1 is required in TECs to produce the cellular and molecular environment needed for normal thymic vascularization, and may mediate a novel TEC-mesenchyme-endothelial form of crosstalk required for fetal thymus organogenesis.
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