ABSTRACT
Lymphoid enhancer factor 1 (LEF-1) and T cell factor 1 (TCF-1) are closely related transcription factors that are both expressed during murine T cell differentiation and that regulate the T cell receptor alpha (TCRalpha) enhancer in transfection assays. Targeted gene disruption of either the Tcf1 or Lef1 gene in mice did not affect TCRalpha gene expression and resulted in an incomplete defect or no defect in thymocyte differentiation. Here, we examine a potential redundancy of these transcription factors by analyzing double-mutant mice. In fetal thymic organ cultures from Lef1-/- Tcf1-/- mice, alpha/beta T cell differentiation is completely arrested at the immature CD8+ single-positive (CD8+ ISP) stage and is markedly impaired at an earlier stage. In addition, we find that sorted CD8+ ISP cells from Lef1-/- Tcf1-/- mice express TCRbeta but show a severely reduced level of TCRalpha gene transcription. Together, these data show that LEF-1 and TCF-1 are redundant in the regulation of T cell differentiation and gene expression.
Subject(s)
DNA-Binding Proteins/physiology , Gene Expression Regulation/physiology , Genes, T-Cell Receptor alpha , Receptors, Antigen, T-Cell, alpha-beta/biosynthesis , T-Lymphocytes/physiology , Transcription Factors/physiology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/physiology , Cell Differentiation/physiology , Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor , Hepatocyte Nuclear Factor 1-alpha , Lymphoid Enhancer-Binding Factor 1 , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, SCID , Organ Culture Techniques , T Cell Transcription Factor 1 , T-Lymphocytes/cytology , T-Lymphocytes/metabolism , Thymus Gland/cytology , Thymus Gland/physiologyABSTRACT
Lymphoid enhancer factor 1 (LEF-1) is a sequence-specific DNA-binding protein that is expressed in pre-B and T lymphocytes of adult mice, and in the neural crest, mesencephalon, tooth germs, whisker follicles, and other sites during embryogenesis. We have generated mice carrying a homozygous germ-line mutation in the LEF-1 gene that eliminates its protein expression and causes postnatal lethality. The mutant mice lack teeth, mammary glands, whiskers, and hair but show no obvious defects in lymphoid cell populations at birth. The LEF-1-deficient mice also lack the mesencephalic nucleus of the trigeminal nerve, the only neural crest-derived neuronal populations. Together, the pattern of these defects suggest an essential role for LEF-1 in the formation of several organs and structures that require inductive tissue interactions.
