Targeted deletion of Eed arrests thymus development

Polycomb group proteins regulate cell fate and differentiation by modifying histones to maintain chromatin in a compacted state that silences expression of inappropriate genes. EED is an essential core component of the Polycomb repressive complex 2 which trimethylates lysine 27 on histone H3. To determine the role of Eed in thymus organogenesis, we excised eed specifically from thymic epithelial cells (TECs) by crossing Eed fl/fl mice with a FoxN1 Cre strain. We found a hypoplastic and highly cystic thymus in four week FoxN1 Cre/+ ; Eed fl/fl mice. Cortical and medullary TECs were depleted in the mutants; however, the cortical compartment was more profoundly affected. TEC depletion was coupled with decreased thymocyte cellularity, which is not surprising given that TECs provide indispensable maturation and survival signals to thymocytes. The thymus and parathyroid glands arise respectively from ventral (Foxn1+) and dorsal (Gcm2+) endodermal progenitors in the 3 rd pharyngeal pouch. We did not observe an alteration in the allocation of endodermal progenitors to a thymus versus parathyroid fate indicating that altered pouch patterning is not responsible for the TEC phenotype. At E15.5, mutant and wildtype fetal thymic lobes were comparable in size and TEC subset composition. However, by E16.5 defects in TEC differentiation and survival are apparent and this phenotype progresses rapidly with age. Current work focuses on the role of eed in maintaining TEC progenitors.