Hedgehog signaling controls thymocyte progenitor homeostasis and differentiation in the thymus.
Commitment of hematopoietic progenitors to the T cell lineage requires the integration of multiple signaling pathways. Evidence has suggested involvement of hedgehog (Hh) signaling in T cell differentiation through its signal transducer smoothened (Smo). However, the precise function of the Hh pathway remains controversial, mainly because T cell-specific in vivo genetic models have not been used. Using pre-T cell-specific, mature T cell-specific and poly(I).poly(C)-inducible deletions of Smo and antagonists of Smo signaling, we report here that Hh is an essential positive regulator of T cell progenitor differentiation. Furthermore, we localize Hh function to a stage preceding pre-T cell receptor signaling, connect Smo signaling to the activity of the Gli1 and Gli2 transcription factors and demonstrate that Hh affects regulators of thymocyte survival and proliferation.
El Andaloussi
Abdeljabar
A
Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, Illinois 60637, USA.
Graves
Stephanie
S
Meng
Fanyong
F
Mandal
Malay
M
Mashayekhi
Mona
M
Aifantis
Iannis
I
D000818:Animals; D002453:Cell Cycle / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D053823:Hedgehog Proteins; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000276:immunology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology
D018076:DNA, Complementary; D053823:Hedgehog Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D015534:Trans-Activators; D014704:Veratrum Alkaloids; C000541:cyclopamine