PT  - JOURNAL ARTICLE
AU  - Jie Li
AU  - Julie Gordon
AU  - Edward L. Y. Chen
AU  - Luying Wu
AU  - Juan Carlos Zúñiga-Pflücker
AU  - Nancy R. Manley
TI  - NOTCH1 signaling establishes the medullary thymic epithelial cell progenitor pool during mouse fetal development
AID  - 10.1101/600817
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 600817
4099  - http://biorxiv.org/content/early/2019/04/05/600817.short
4100  - http://biorxiv.org/content/early/2019/04/05/600817.full
AB  - The cortical and medullary thymic epithelial cell (cTEC and mTEC) lineages are essential for inducing T cell lineage commitment, T cell positive selection and the establishment of self-tolerance, but the mechanisms controlling their fetal specification and differentiation are poorly understood. Here, we show that Notch signaling is required to specify and expand the mTEC lineage. Notch1 is expressed by and active in TEC progenitors. Deletion of Notch1 in TECs resulted in depletion of mTEC progenitors and dramatic reductions in mTECs during fetal stages, consistent with defects in mTEC specification and progenitor expansion. Conversely, forced Notch signaling in all TEC resulted in widespread expression of mTEC progenitor markers and profound defects in TEC differentiation. In addition, lineage-tracing analysis indicated that all mTECs have a history of receiving a Notch signal, consistent with Notch signaling occurring in mTEC progenitors. Interestingly, this lineage analysis also showed that cTECs are divided between Notch lineage-positive and lineage-negative populations, identifying a previously unknown complexity in the cTEC lineage.