Investigation of the mechanisms of transcriptional regulation of thymic epithelial cell fate

The thymus is required for production of a functional, self-tolerant T cell repertoire. Because the thymus degenerates early in life, a process called age-related thymic involution, there is a need for therapies that could boost or replace thymus function in a variety of clinical indications. FOXN1 is the transcription factor that orchestrates thymus development beyond initial formation of the thymus primordium. However, the mechanisms that regulate Foxn1 expression during thymus development, and via which FOXN1 establishes the thymic epithelial lineage differentiation programme, are not yet understood. This project will test the hypothesis that four genes, Pax1, Pax9, Hoxa3 and Gata3, form the core gene regulatory network that initiates Foxn1 transcription in the developing thymus. It will also begin to determine whether FOXN1 functions as a pioneer factor, or as a classical transcriptional activator, by testing whether FOXN1 function in thymus development can be substituted by other FOX family members.