Canonical Notch signaling controls the early thymic epithelial progenitor cell state and emergence of the medullary epithelial lineage in fetal thymus development

Abstract

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.

Transcriptional and epigenetic regulation in thymic epithelial cells*

“…Constitutive KO Deficiency in p63 resulted in thymic hyploplasia during embryonic development 91,92 Pou2f3 Constitutive KO Pou2f3 deficiency resulted in loss of thymic tuft cells 32,33 RBPJ Cre-Foxn1 Rbpj fl/fl , CreER-Foxa2 Notch fl/fl , Cre-Foxn1 Rosa N1−IC , RBPJ fl/fl Cre-Foxn1; Rosa rtTA ; Tet on -RBPJ-HA Deficiency of either Notch1 or RBPJ inhibited the establishment of mTEC progenitor cells during fetal development, and reduced the mTEC compartment postnatally 179,180…”

Circulating mature dendritic cells homing to the thymus promote thymic epithelial cells involution via the Jagged1/Notch3 axis

“…Similarly, loss of Notch signaling functions resulted in mTECs hypoplasia. However, the maturation of TEC progenitors whose Notch signaling was defected would be inhibited after Notch signaling function was restored [ 10 ]. Goldfarb et al confirmed that decreasing Notch signaling was required in the later stages of mTECs differentiation.…”

“…Both the increase in sex steroids and the decrease of growth hormones induce thymic involution with aging [ 9 ]. Several signaling pathways, including Notch signaling [ 10 ], Wnt/β-catenin [ 11 ], and bone morphogenetic protein (BMP) signaling [ 12 ], are also involved in thymic development. Notch signaling plays critical roles in cell development, homeostasis, and disease processes, such as stem cell renewal, embryonic and organic development, cardiomyopathy, oncogenesis, etc [ 13 ].…”

“…Previous studies showed that the Notch signaling is essential for maintaining thymic epithelial progenitor cells and medullary epithelial cells in fetal thymic development [ 10 ]. Mice carrying mutations in Jagged2, one of the ligands of Notch receptors, exhibited impaired thymic development and morphology [ 17 ].…”

Epigenetic modifications in thymic epithelial cells: an evolutionary perspective for thymus atrophy

“…Therefore we focus on the signaling pathway on mTECs maturation. Firstly, the activation of the Notch signaling pathway is indispensable for the specification of the earliest mTECs lineage [ 20 ]. The deletion of Notch1 in TECs during the embryonic period contributes to the depletion of mTEPCs and a significant loss of mTECs [ 21 ].…”