Involvement of Prep1 in the alphabeta T-cell receptor T-lymphocytic potential of hematopoietic precursors.
Prep1 is a homeodomain transcription factor that acts by dimerizing with Pbx. Since Prep1 null embryos die at gastrulation, we studied Prep1(i/i) hypomorphic mice to study the physiological role of Prep1. A low percentage of homozygous Prep1(i/i) mice survived at birth, and their postnatal functions could be investigated. Reduced Prep1 expression caused an abnormal thymic T-cell development: increased CD4(-) CD8(-) double-negative thymocytes, decrease in alphabetaTCR(high) cells (cells with high levels of the alphabetaTau-cell receptor [alphabetaTCR]) and CD4(+) and CD8(+) single-positive (SP) thymocytes, and increase in gammadeltaTCR cells. Peripheral lymphoid organs of Prep1(i/i) mice contained fewer alphabetaTCR mature T cells and more gammadeltaTCR T cells than wild-type littermates. Moreover, Prep1(i/i) CD4(+) CD8(+) double-positive thymocytes underwent more apoptosis, and SP thymocytes proliferated less than control littermates. Mice that were lethally irradiated and then had Prep1(i/i) fetal liver cells transplanted showed the same defects as the Prep1(i/i) mice did. Among PBC family members, Pbx2 and very low levels of Pbx3 were observed in the thymi of wild-type mice. In Prep1(i/i) mice, the level of Pbx2 protein was profoundly decreased, while for Pbx3 no definitive conclusion could be reached. Therefore, the deficient postnatal T-lymphocytic potential of the Prep1 hematopoietic progenitors depends on the combined, not compensated, absence of Prep1 and at least Pbx2.
Penkov
Dmitri
D
Molecular Genetics Unit, Università Vita Salute San Raffaele, Milan, Italy.
Di Rosa
Patrizia
P
Fernandez Diaz
Luis
L
Basso
Veronica
V
Ferretti
Elisabetta
E
Grassi
Fabio
F
Mondino
Anna
A
Blasi
Francesco
F
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development*
D000945:Antigens, Differentiation, T-Lymphocyte; D018398:Homeodomain Proteins; C490382:Pbx2 protein, mouse; C491412:Pknox1 protein, mouse; D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta