The Hedgehog receptor Patched controls lymphoid lineage commitment.
A first step in hematopoiesis is the specification of the lymphoid and myeloid lineages from multipotent progenitor cells in the bone marrow. Using a conditional ablation strategy in adult mice, we show that this differentiation step requires Patched (Ptch), the cell surface-bound receptor for Hedgehog (Hh). In the absence of Ptch, the development of T- and B-lymphoid lineages is blocked at the level of the common lymphoid progenitor in the bone marrow. Consequently, the generation of peripheral T and B cells is abrogated. Cells of the myeloid lineage develop normally in Ptch mutant mice. Finally, adoptive transfer experiments identified the stromal cell compartment as a critical Ptch-dependent inducer of lymphoid versus myeloid lineage commitment. Our data show that Ptch acts as a master switch for proper diversification of hematopoietic stem cells in the adult organism.
Uhmann
Anja
A
Institute of Human Genetics, Georg August University of Göttingen, Göttingen, Germany.
Dittmann
Kai
K
Nitzki
Frauke
F
Dressel
Ralf
R
Koleva
Milena
M
Frommhold
Anke
A
Zibat
Arne
A
Binder
Claudia
C
Adham
Ibrahim
I
Nitsche
Mirko
M
Heller
Tanja
T
Armstrong
Victor
V
Schulz-Schaeffer
Walter
W
Wienands
Jürgen
J
Hahn
Heidi
H
D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006410:Hematopoiesis; D016130:Immunophenotyping; D019426:Integrases / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology; D013997:Time Factors
D004268:DNA-Binding Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C499308:Rag2 protein, mouse; D011956:Receptors, Cell Surface; C045073:Cre recombinase; D019426:Integrases