AUTHOR=Hirano Ken-ichi , Hosokawa Hiroyuki , Yahata Takashi , Ando Kiyoshi , Tanaka Masayuki , Imai Jin , Yazawa Masaki , Ohtsuka Masato , Negishi Naoko , Habu Sonoko , Sato Takehito , Hozumi Katsuto 

TITLE=Dll1 Can Function as a Ligand of Notch1 and Notch2 in the Thymic Epithelium

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.852427

DOI=10.3389/fimmu.2022.852427

ISSN=1664-3224

ABSTRACT=<p>T-cell development in the thymus is dependent on Notch signaling induced by the interaction of Notch1, present on immigrant cells, with a Notch ligand, delta-like (Dll) 4, on the thymic epithelial cells. Phylogenetic analysis characterizing the properties of the Dll4 molecule suggests that Dll4 emerged from the common ancestor of lobe- and ray-finned fishes and diverged into bony fishes and terrestrial organisms, including mammals. The thymus evolved in cartilaginous fishes before Dll4, suggesting that T-cell development in cartilaginous fishes is dependent on Dll1 instead of Dll4. In this study, we compared the function of both Dll molecules in the thymic epithelium using <italic>Foxn1-cre</italic> and <italic>Dll4</italic>-floxed mice with conditional transgenic alleles in which the <italic>Dll1</italic> or <italic>Dll4</italic> gene is transcribed after the cre-mediated excision of the stop codon. The expression of Dll1 in the thymic epithelium completely restored the defect in the <italic>Dll4</italic>-deficient condition, suggesting that Dll1 can trigger Notch signaling that is indispensable for T-cell development in the thymus. Moreover, using bone marrow chimeras with <italic>Notch1</italic>- or <italic>Notch2</italic>-deficient hematopoietic cells, we showed that Dll1 is able to activate Notch signaling, which is sufficient to induce T-cell development, with both the receptors, in contrast to Dll4, which works only with Notch1, in the thymic environment. These results strongly support the hypothesis that Dll1 regulates T-cell development <italic>via</italic> Notch1 and/or Notch2 in the thymus of cartilaginous fishes and that Dll4 has replaced Dll1 in inducing thymic Notch signaling <italic>via</italic> Notch1 during evolution.</p>