The interaction of the Wnt and Notch pathways modulates natural killer versus T cell differentiation.
The Wnt and Notch signaling pathways have been independently shown to play a critical role in regulating hematopoietic cell fate decisions. We previously reported that induction of Notch signaling in human CD34(+)CD38(-) cord blood cells by culture with the Notch ligand Delta 1 resulted in more cells with T or natural killer (NK) lymphoid precursor phenotype. Here, we show that addition of Wnt3a to Delta 1 further increased the percentage of CD34(-)CD7(+) and CD34(-)CD7(+)cyCD3(+) cells with increased expression of CD3 epsilon and preT alpha. In contrast, culture with Wnt3a alone did not increase generation of CD34(-)CD7(+) precursors or expression of CD3 epsilon or preT alpha gene. Furthermore, Wnt3a increased the amount of activated Notch1, suggesting that Wnt modulates Notch signaling by affecting Notch protein levels. In contrast, addition of a Wnt signaling inhibitor to Delta 1 increased the percentage of CD56(+) NK cells. Overall, these results demonstrate that regulation of Notch signaling by the Wnt pathway plays a critical role in differentiation of precursors along the early T or NK differentiation pathways. Disclosure of potential conflicts of interest is found at the end of this article.
Aoyama
Keisuke
K
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D2-373, Seattle, Washington 98109, USA.
Delaney
Colleen
C
Varnum-Finney
Barbara
B
Kohn
Aimee D
AD
Moon
Randall T
RT
Bernstein
Irwin D
ID
D015703:Antigens, CD / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D005312:Fetal Blood / Q000166:cytology; D017930:Genes, Reporter; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000166:cytology*; D008565:Membrane Proteins / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology*; D014161:Transduction, Genetic; D051153:Wnt Proteins / Q000494:pharmacology / Q000502:physiology*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D015703:Antigens, CD; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051880:Receptors, Notch; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C064045:delta protein