Abstract
ObjectivePrep1 and Pbx2 are the main homeodomain DNA-binding proteins of the TALE (three amino acid loop extension) family expressed in the thymus. We previously reported reduced Pbx2 expression and defective thymocyte maturation in Prep1 hypomorphic mice. To further investigate the role of this homeodomain DNA-binding protein in T cell development, we generated transgenic mice expressing the N-terminal fragment of Pbx1 (Pbx1NT) under the control of the Lck proximal promoter.Principal FindingsPbx1NT causes Prep1 cytosolic sequestration, abolishes Prep1-dependent DNA-binding activity and results in reduced Pbx2 expression in developing thymocytes. Transgenic thymi reveal increased numbers of CD4− CD8− CD44− (DN3 and DN4) thymocytes, due to a higher frequency of DN2 and DN4 Pbx1NT thymocytes in the S phase. Transgenic thymocytes however do not accumulate at later stages, as revealed by a normal representation of CD4/CD8 double positive and single positive thymocytes, due to a higher rate of apoptotic cell death of DN4 Pbx1NT thymocytes.ConclusionThe results obtained by genetic (Prep1 hypomorphic) and functional (Pbx1NT transgenic) inactivation of Prep1 support nonredundant roles for this homeodomain protein during different stages of T cell development.
Highlights
Prep1 is a transcription factor belonging to the TALE family of homeodomain proteins, which in vertebrates comprises the PBC (Pbx1 to Pbx4), Prep (Prep1 and Prep2) and Meis (Meis1, Meis2 and Meis3) subfamilies [1]
The results obtained by genetic (Prep1 hypomorphic) and functional (Pbx1NT transgenic) inactivation of Prep1 support nonredundant roles for this homeodomain protein during different stages of T cell development
To investigate the relative contribution of cytosolic and nuclear Prep1 to T cell development we generated TG mice expressing the Nterminal fragment of a Pbx1 able to sequestrer Prep1 in the cytosol [5], under the control of the lck proximal promoter, which is active in T cells [9]
Summary
Prep is a transcription factor belonging to the TALE (threeamino-acid loop extension) family of homeodomain proteins, which in vertebrates comprises the PBC (Pbx to Pbx4), Prep (Prep and Prep2) and Meis (Meis, Meis and Meis3) subfamilies [1]. Prep is present in a cytoplasmic and a nuclear localizations in different hematopoietic precursors [2] and plays a central role starting from the earliest stages of embryonic development since a Prep null mutation causes lethality around gastrulation We have recently generated Prep hypomorphic mice (Prep1i/i), in which the level of Prep is reduced to about 2–10% of wild type (wt), and found that Prep1i/i embryos die (in 80% of the cases) at E17.5-P0 with anemia and major defects in oculogenesis and angiogenesis [3,4]. The other 20% of the embryos develop to term and live a normallength life. Prep1i/i mice show a decreased number of singlepositive thymocytes due to a higher propensity of DP (CD4+ CD8+) cells to undergo apoptotic cell death [3]
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