Miz-1 is required to coordinate the pre-TCR-dependent transitional step in DN3/DN4 thymocytes. (160.1)

Abstract

Abstract Miz-1 (Myc-interacting zinc finger-1) is a BTB/POZ domain transcription factor that can activate or repress gene transcription. To explore the function of Miz-1, we have generated mice that express a non-functional protein lacking the POZ domain, Miz-1ΔPOZ. These mice show a very small thymus owing to a dramatic reduction of early T cell progenitors and DN4 pre-T cells. DN1-3 cells have higher apoptotic rate indicating that Miz-1 is coordinating survival signals. Miz-1ΔPOZ mice also have a DN3/DN4 transitional block and DN3 cells showed a dramtic up-regulation of the cell cycle regulator p21Waf1. Surprisingly, neither the introduction of a Bcl-2 transgene nor the deletion of p21Waf1 rescued the DN3/DN4 block in Miz-1ΔPOZ mice. The block at the pre-TCR-dependent selection stage rather suggested that Miz-1 might regulate pre-TCR signaling. Although the pre-TCR signaling does not seem to be altered by the expression of a non-functional Miz-1, the intracellular expression of the TCRβ is reduced. Introduction of a rearranged TCR transgene rescued the DN3/DN4 cell numbers and their function in Miz-1ΔPOZ mice. Our data suggest that Miz-1 is required for the transport or the stability of the pre-TCR in order to support the proliferative burst of DN3 cells. Comparative gene expression analysis will determine which are the direct effector genes of Miz-1 and contribute to a better understanding of the critical factors involved in this precise step of T cell development.