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Involvement of Prep1 in the ß T-Cell Receptor T-Lymphocytic Potential of Hematopoietic Precursors

Dmitri Penkov,^1,2, Patrizia Di Rosa,^1,2 Luis Fernandez Diaz,^1,2 Veronica Basso,³ Elisabetta Ferretti,^1,2, Fabio Grassi,⁴ Anna Mondino,³ and Francesco Blasi^1,2*

Molecular Genetics Unit, Università Vita Salute San Raffaele, via Olgettina 58, 20132 Milan, Italy,¹ IFOM (FIRC Institute of Molecular Oncology), via Adamello 14, 20016 Milan, Italy,² Lymphocyte Activation Unit, Istituto Scientifico San Raffaele, Milan, Italy;,³ Institute of Research in Biomedicine, V. V. Vela, Bellinzona, Switzerland⁴

Received 13 July 2005/ Returned for modification 28 August 2005/ Accepted 23 September 2005

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 ßTCR^high cells (cells with high levels of the ßT-cell receptor [ßTCR]) and CD4⁺ and CD8⁺ single-positive (SP) thymocytes, and increase in TCR cells. Peripheral lymphoid organs of Prep1^i/i mice contained fewer ßTCR mature T cells and more TCR 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.

Present address: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia.

Present address: Department of Cell and Developmental Biology, Weill Medical College, Cornell University, New York, NY 10021.

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