Discovery of transcriptional regulators of thymic microenvironment formation
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Thymic epithelial cells (TECs) are the major component of the thymic microenvironment that supports T cell development. Different TEC subtypes reside in different functional zones of the thymus and carry their own gene expression profiles and specialized functions in supporting different stages of T cell development. However, in contrast to the known phenotypic and functional complexities of TECs, the molecular mechanisms that enable the development of this elaborate thymic epithelial network and the formation of the thymic microenvironment is still poorly understood. A forkhead transcription factor, Foxn1, has been known as the master control gene for thymus development. However, evidence suggests that additional regulators are to be revealed in the regulatory network of TEC differentiation. My dissertation focused on identifying additional transcription regulators required for TEC differentiation independent of or in collaboration with Foxn1. The first part of this dissertation is a screen for transcription factors with potential functions in thymus development. We identified several factors with early localized expression patterns in the third pharyngeal pouch endoderm where the thymus rudiment is formed during mouse embryogenesis, suggesting that these genes might be involved in early patterning of the pouch. Furthermore, we found two transcription factors, Foxg1 and Islet1 that are expressed in developing TECs through out embryogenesis and postnatal life. These factors are candidates for potential regulator of TEC differentiation and function. In the later part of this dissertation, we tested the function of one candidate factor, Foxg1, during thymus organogenesis by analyzing Foxg1 mutant mice. Our results showed that Foxg1 is required for normal thymic microenvironment formation because Foxg1 mutant thymus becomes progressively hypoplastic during embryogenesis and has a disrupted thymic epithelial network. Our data also suggest that Foxg1 expression and function is independent of Foxn1, and this thymus atrophy is not caused by the same mechanism by which loss of Foxg1 is known to cause defective telencephalon development. Finally we show that Foxg1 is required for induction of an essential cytokine, IL-7, expression in the TECs and lack of IL-7 is responsible for part but not all phenotypes of Foxg1 mutant thymus.