Miz-1 Is Required To Coordinate the Expression of TCRβ and p53 Effector Genes at the Pre-TCR “β-Selection” Checkpoint

Miz-1 is a Broad-complex, Tramtrack and Bric-a-brac/pox virus zinc finger domain (BTB/POZ)-containing protein expressed in lymphoid precursors that can activate or repress transcription. We report in this article that mice expressing a nonfunctional Miz-1 protein lacking the BTB/POZ domain (Miz-1ΔPOZ) have a severe differentiation block at the pre-T cell “β-selection” checkpoint, evident by a drastic reduction of CD4−CD8− double-negative–3 (DN3) and DN4 cell numbers. T cell-specific genes including Rag-1 , Rag-2 , CD3e , pTα , and TCRβ are expressed in Miz-1–deficient cells and V(D)J recombination is intact, but few DN3/DN4 cells express a surface pre-TCR. Miz-1–deficient DN3 cells are highly apoptotic and do not divide, which is consistent with enhanced expression of p53 target genes such as Cdkn1a , PUMA , and Noxa . However, neither coexpression of the antiapoptotic protein Bcl2 nor the deletion of p21CIP1 nor the combination of both relieved Miz-1–deficient DN3/DN4 cells from their differentiation block. Only the coexpression of rearranged TCRαβ and Bcl2 fully rescued Miz-1–deficient DN3/DN4 cell numbers and enabled them to differentiate into DN4TCRβ+ and double-positive cells. We propose that Miz-1 is a critical factor for the β-selection checkpoint and is required for both the regulation of p53 target genes and proper expression of the pre-TCR to support the proliferative burst of DN3 cells during T cell development.