NDRG3 is a novel regulator of T and B cell development with phosphorylation-specific activity and phenotypes.

Abstract Common lymphoid progenitors (CLPs) in the bone marrow give rise to both T and B cells, but mechanisms underpinning downstream cell fate decisions have yet be fully elucidated. We identified N-Myc Downstream Regulated Gene 3 (NDRG3) - a highly conserved regulator of Wnt/B-catenin signaling as novel lymphocyte substrate Akt kinase. To determine effect NDRG3 phosphorylation, hematopoietic stem cells (HSCs) overexpressing phospho-null (S331A) or phospho-mimetic (S331E) mutant were transferred into lethally irradiated mice followed by analysis reconstituted immune populations. S331A-expressing developed 3:1 preference for while those expressing S331E had 9:1 fate. further probe effects we mouse model that utilizes IL-7Ra-driven Cre express NDRG3-S331A from endogenous locus. thymocytes displayed faster transition through preTCR TCR checkpoints. Given importance TCF1 thymocyte development, crossed TCF1-GFP TCF1-RE-GFP reporter examine on Wnt/TCF1 pathway. In spleen, increase at expense cells. Within population, exhibited 4:1 marginal zone follicular was associated with increased levels IRF4 IRF8 transcription factors, which are necessary proper development. These data reveal controls developmental kinetics pathways governing development maturation phosphorylation-dependent manner. Supported NIH grant R01 AI089805 training fellowship Burroughs Wellcome Fund.