Open AccessCanonical Notch signaling controls the early thymic epithelial progenitor cell state and emergence of the medullary epithelial lineage in fetal thymus development
Author(s) -
Dong Liu,
Anastasia I. Kousa,
Kathy E. O’Neill,
Paul Rouse,
Martyna Popis,
Alison Farley,
Simon R. Tomlinson,
Svetlana Ulyanchenko,
François Guillemot,
Philip A. Seymour,
Mette C. Jørgensen,
Palle Serup,
Ute Koch,
Freddy Radtke,
C. Clare Blackburn
Publication year - 2020
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.15
H-Index - 36
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.178582
Subject(s) - biology , notch signaling pathway , microbiology and biotechnology , progenitor cell , progenitor , lineage (genetic) , stem cell , cellular differentiation , regulator , chordate , stroma , autoimmune regulator , immunology , signal transduction , genetics , vertebrate , gene , antibody , immunohistochemistry , autoimmune disease
Thymus function depends on the epithelial compartment of the thymic stroma. Cortical thymic epithelial cells (cTECs) regulate T cell lineage commitment and positive selection, while medullary (m) TECs impose central tolerance on the T cell repertoire. During thymus organogenesis, these functionally distinct sub-lineages are thought to arise from a common thymic epithelial progenitor cell (TEPC). However, the mechanisms controlling cTEC and mTEC production from the common TEPC are not understood. Here, we show that emergence of the earliest mTEC lineage-restricted progenitors requires active NOTCH signaling in progenitor TEC and that, once specified, further mTEC development is NOTCH independent. In addition, we demonstrate that persistent NOTCH activity favors maintenance of undifferentiated TEPCs at the expense of cTEC differentiation. Finally, we uncover a cross-regulatory relationship between NOTCH and FOXN1, a master regulator of TEC differentiation. These data establish NOTCH as a potent regulator of TEPC and mTEC fate during fetal thymus development, and are thus of high relevance to strategies aimed at generating/regenerating functional thymic tissue in vitro and in vivo .