Notch/Delta signaling constrains reengineering of pro-T cells by PU.1.
PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through beta-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo beta-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment.
Franco
Christopher B
CB
Division of Biology 156-29, California Institute of Technology, Pasadena, CA 91125, USA.
Scripture-Adams
Deirdre D
DD
Proekt
Irina
I
Taghon
Tom
T
Weiss
Angela H
AH
Yui
Mary A
MA
Adams
Stephanie L
SL
Diamond
Rochelle A
RA
Rothenberg
Ellen V
EV
D000818:Animals; D019070:Cell Lineage; D002470:Cell Survival; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D000099232:Proto-Oncogene Protein Spi-1
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051881:Receptor, Notch1; D015375:Receptors, Interleukin-2; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C497762:Notch1 protein, mouse