title: Conversion of the thymus into a bipotent lymphoid organ by replacement of FOXN1 with its paralog, FOXN4.
abstract: The thymus is a lymphoid organ unique to vertebrates, and it provides a unique microenvironment that facilitates the differentiation of immature hematopoietic precursors into mature T cells. We subjected the evolutionary trajectory of the thymic microenvironment to experimental analysis. A hypothetical primordial form of the thymus was established in mice by replacing FOXN1, the vertebrate-specific master regulator of thymic epithelial cell function, with its metazoan ancestor, FOXN4, thereby resetting the regulatory and coding changes that have occurred since the divergence of these two paralogs. FOXN4 exhibited substantial thymopoietic activity. Unexpectedly, histological changes and a functional imbalance between the lymphopoietic cytokine IL7 and the T cell specification factor DLL4 within the reconstructed thymus resulted in coincident but spatially segregated T and B cell development. Our results identify an evolutionary mechanism underlying the conversion of a general lymphopoietic organ to a site of exclusive T cell generation.
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Swann
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Annelies
authors.initials: A
authors.lastname: Weyn
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagakubo
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Bleul
authors.affiliation: Comparative Genomics Laboratory, Center for Genetic Resource Information, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Toyoda
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Happe
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Netuschil
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Hess
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Haas-Assenbaum
authors.affiliation: Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Taniguchi
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schorpp
authors.affiliation: Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany. Electronic address: boehm@immunbio.mpg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boehm
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005818:Genetic Engineering; D006411:Hematopoiesis, Extramedullary; D008221:Lymphoid Tissue; D038041:Lymphopoiesis; D051379:Mice; D008822:Mice, Transgenic; D009990:Oryzias; D010802:Phylogeny; D013601:T-Lymphocytes / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D005136:Eye Proteins; D051858:Forkhead Transcription Factors; C438622:Foxn4 protein, mouse; C090140:Whn protein