Stabilized beta-catenin in thymic epithelial cells blocks thymus development and function.
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.
Zuklys
Saulius
S
Department of Clinical-Biological Sciences, Laboratory of Pediatric Immunology, University of Basel, and Basel University Children's Hospital, Basel, Switzerland.
Gill
Jason
J
Keller
Marcel P
MP
Hauri-Hohl
Mathias
M
Zhanybekova
Saule
S
Balciunaite
Gina
G
Na
Kyung-Jae
KJ
Jeker
Lukas T
LT
Hafen
Katrin
K
Tsukamoto
Noriyuki
N
Amagai
Takashi
T
Taketo
Makoto M
MM
Krenger
Werner
W
Holländer
Georg A
GA
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
D051858:Forkhead Transcription Factors; D006131:Growth Inhibitors; C090140:Whn protein; D051153:Wnt Proteins; D051176:beta Catenin