The development of lymphoid lineages from pluripotent stem cells is a poorly understood process. The identification of lymphoid committed precursors is not only of academic but also of clinical interest because of their faster immunorestorative potential when compared to hemopoietic stem cells (HSC) after transplantation into immunodeficient hosts. Previous analysis of the expression of the pre-TCRa (pTa) chain, which forms the pre-TCR in association with the TCRb chain, has shown its presence in precursors of T cells but not in pluripotent hemopoietic stem cells. This suggests that expression of the pTa gene marks lymphoid precursors. Therefore, we propose to isolate lymphoid precursors with the aid of reporter genes that are controlled by pTa promoter and enhancer elements. Our initial data indicate that such reporters can be expressed in lymphoid committed precursors in the bone marrow that are able to generate all lymphoid lineages but no myeloid cells. We propose to subdivide the reporter gene expressing cells by a variety of cell surface molecules that are involved in and correlate with lymphoid development. We will then reveal the developmental potential of these subsets in order to generate a detailed picture of lymphoid commitment in fetal and adult lymphopoiesis and to identify branching points of the various lineages. We will further characterize developmental stages with regard to expression and essential role of transcription factors involved in lineage commitment.
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