c-Myc mediates pre-TCR-induced proliferation but not developmental progression.
Constitutive and cell-autonomous signals emanating from the pre-T-cell receptor (pre-TCR) promote proliferation, survival and differentiation of immature thymocytes. We show here that induction of pre-TCR signaling resulted in rapid elevation of c-Myc protein levels. Cre-mediated thymocyte-specific ablation of c-Myc in CD25(+)CD44(-) thymocytes reduced proliferation and cell growth at the pre-TCR checkpoint, resulting in thymic hypocellularity and a severe reduction in CD4(+)CD8(+) thymocytes. In contrast, c-Myc deficiency did not inhibit pre-TCR-mediated differentiation or survival. Myc(-/-) double-negative (DN) 3 cells progressed to the double-positive (DP) stage and up-regulated TCRalphabeta surface expression in the absence of cell proliferation, in vivo as well as in vitro. These observations indicate that distinct signals downstream of the pre-TCR are responsible for proliferation versus differentiation, and demonstrate that c-Myc is only required for pre-TCR-induced proliferation but is dispensable for developmental progression from the DN to the DP stage.
Dose
Marei
M
Tufts-New England Medical Center, 750 Washington St, Tufts-NEMC no. 5602, Boston, MA 02111, USA.
Khan
Irum
I
Guo
Zhuyan
Z
Kovalovsky
Damian
D
Krueger
Andreas
A
von Boehmer
Harald
H
Khazaie
Khashayarsha
K
Gounari
Fotini
F
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D018076:DNA, Complementary / Q000235:genetics; D016259:Genes, myc; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
D018076:DNA, Complementary; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell