title: Runx1/Cbfβ2 complexes are required for lymphoid tissue inducer cell differentiation at two developmental stages.
abstract: Hematopoietic lymphoid tissue inducer (LTi) cells are essential for the development of secondary lymphoid tissues including lymph nodes and Peyer's patches. Two transcription factors, the helix-loop-helix inhibitor Id2 and the retinoic acid-related orphan receptor γt (Rorγt), have been shown to be crucial for LTi cell development. However, it remains unclear how the specification of multipotent hematopoietic progenitor cells toward the LTi lineage is programmed. In this study, we report impaired lymphoid tissue organogenesis in mice in which the function of Runx1/Cbfβ transcription factor complexes was attenuated by the loss of either the distal promoter-derived Runx1 or Cbfβ2 variant protein. We found that LTi progenitors in fetal liver, defined previously as a lineage marker-negative α4β7 integrin (α4β7)(+) IL-7R α-chain (IL-7Rα)(+) population, can be subdivided into Rorγt-expressing IL-7Rα(high) cells and nonexpressing IL-7Rα(mid) cells. Whereas Id2 and Rorγt are required to direct α4β7(+)IL-7Rα(mid) cells to become α4β7(+)IL-7Rα(high) cells, Runx1/Cbfβ2 complexes are necessary for the emergence of α4β7(+)IL-7Rα(mid) cells. In addition, the loss of Cbfβ2, but not P1-Runx1, resulted in an inefficient upregulation of Rorγt in residual α4β7(+)IL-7Rα(+) LTi cells at anlagen. Our results thus revealed that Runx1/Cbfβ2 complexes regulate the differentiation of LTi cells at two stages: an early specification of hematopoietic progenitors toward the LTi lineage and a subsequent activation of Rorγt expression at anlagen.
authors.affiliation: Laboratory for Transcriptional Regulation, Research Center for Allergy and Immunology, RIKEN, Yokohama 230-0045, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tachibana
authors.forename: Mari
authors.initials: M
authors.lastname: Tenno
authors.forename: Chieko
authors.initials: C
authors.lastname: Tezuka
authors.forename: Machiko
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Yoshida
authors.forename: Ichiro
authors.initials: I
authors.lastname: Taniuchi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D050676:Core Binding Factor Alpha 2 Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050658:Core Binding Factor beta Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014644:Genetic Variation / Q000276:immunology; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000196:embryology / Q000276:immunology / Q000473:pathology; D008221:Lymphoid Tissue / Q000166:cytology / Q000196:embryology / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D039902:Multipotent Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
chemical_list: C493693:Cbfb protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C493726:Runx1 protein, mouse