Involvement of Prep1 in the αβTCR 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 Prep1i/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 αβTCRhigh cells (cells with high levels of the α-cell receptor [αβTCR]) and CD4+ and CD8+ single-positive (SP) thymocytes, and increase in γδTCR cells. Peripheral lymphoid organs of Prep1 i/i mice contained fewer αβTCR mature T cells and more γδTCR 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 Prep1i/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 Prep1i/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. Copyright