Loss of foxg1 in thymic epithelial cells leads to thymus hypoplasia in fetal and adult mice and a decrease in the expression of the essential cytokine il-7
Jarvis, Barton Rodney
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The thymus is responsible for providing the necessary microenvironment for the production of a self-restricted, self-tolerant T-cell pool. These T-cells are necessary for the function of an adaptive immune system. Thymic epithelial cells (TEC) are the major component of the microenvironment and are essential for providing signals to the developing thymocytes. However, the genetic networks and signaling pathways responsible for proliferation, differentiation, and survival of TEC are still being uncovered. The transcription factor, Foxn1, has been called the master regulator of TEC and is essential for thymus development. Although, some evidence has shown that there are some aspects of thymus development which are not dependent on Foxn1. Our lab previously identified expression of the transcription factor, Foxg1, in thymus and showed it to be necessary for normal thymus development by controlling Foxn1-independent mechanisms of TEC differentiation, survival, and regulation of the essential cytokine IL-7. This dissertation presents further analysis of the phenotypes caused by loss of Foxg1. Specifically, I utilized a conditional loss of function model by deleting Foxg1 in TEC (Foxg1CKO). I examined the phenotypes of these mutants and show that the defects present in the Foxg1 null mice are also present in the Foxg1CKO at embryonic and postnatal stages, namely thymic hypoplasia, defective differentiation, and increased apoptosis. I also show that Foxg1 is not necessary for initiation of IL-7 but that it is necessary for normal expression levels of this cytokine in TEC. Furthermore, I provide preliminary evidence that suggests the regulation of IL-7 during early thymus organogenesis is due to interactions between Foxg1 and the transcription factor Hoxa3. Finally, I discuss possible interactions between Foxg1 and several signaling pathways present in the thymus that Foxg1 has been shown to directly interact with in the developing telencephalon.