title: Stabilized beta-catenin in thymic epithelial cells blocks thymus development and function.
abstract: Thymic T cell development is dependent on a specialized epithelial microenvironment mainly composed of cortical and medullary thymic epithelial cells (TECs). The molecular programs governing the differentiation and maintenance of TECs remain largely unknown. Wnt signaling is central to the development and maintenance of several organ systems but a specific role of this pathway for thymus organogenesis has not yet been ascertained. In this report, we demonstrate that activation of the canonical Wnt signaling pathway by a stabilizing mutation of beta-catenin targeted exclusively to TECs changes the initial commitment of endodermal epithelia to a thymic cell fate. Consequently, the formation of a correctly composed and organized thymic microenvironment is prevented, thymic immigration of hematopoietic precursors is restricted, and intrathymic T cell differentiation is arrested at a very early developmental stage causing severe immunodeficiency. These results suggest that a precise regulation of canonical Wnt signaling in thymic epithelia is essential for normal thymus development and function.
authors.affiliation: Department of Clinical-Biological Sciences, Laboratory of Pediatric Immunology, University of Basel, and Basel University Children's Hospital, Basel, Switzerland.
authors.forename: Saulius
authors.initials: S
authors.lastname: Zuklys
authors.forename: Jason
authors.initials: J
authors.lastname: Gill
authors.forename: Marcel P
authors.initials: MP
authors.lastname: Keller
authors.forename: Mathias
authors.initials: M
authors.lastname: Hauri-Hohl
authors.forename: Saule
authors.initials: S
authors.lastname: Zhanybekova
authors.forename: Gina
authors.initials: G
authors.lastname: Balciunaite
authors.forename: Kyung-Jae
authors.initials: KJ
authors.lastname: Na
authors.forename: Lukas T
authors.initials: LT
authors.lastname: Jeker
authors.forename: Katrin
authors.initials: K
authors.lastname: Hafen
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Tsukamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Amagai
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Werner
authors.initials: W
authors.lastname: Krenger
authors.forename: Georg A
authors.initials: GA
authors.lastname: Holländer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D004707:Endoderm / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics; D018390:Gene Targeting; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology
chemical_list: D051858:Forkhead Transcription Factors; D006131:Growth Inhibitors; C090140:Whn protein; D051153:Wnt Proteins; D051176:beta Catenin