摘要：SummaryOstm1mutations cause the severe form of osteopetrosis with bone marrow deficiency in humans and mice, yet a role in T cell ontogeny remains to be determined. Herein, we show that thymi of theOstm1-null mice (gl/gl) from P8-to-P15 become markedly hypocellular with disturbed architecture. Analysis of gl/gl early T cell program determined a major decrease of 3-fold in bone marrow common lymphoid precursors (CLP), 35-fold in early thymic precursors (ETPs) and 100-fold in T cell double positive subpopulations.Ostm1ablation in T cell double negative (DN) also appears to induce fast-paced differentiation kinetics with a transitory intermediate CD44+CD25intsubpopulation. Transgenic targetingOstm1expression from the gl/gl DN1 population partially rescued T cell subpopulations from ETP onwards and normalized the accelerated DN differentiation, indicating a cell-autonomous role forOstm1. Transcriptome of early DN1 population identified anOstm1crosstalk with aFoxo1-Klf2-S1pr1-Gnai1-Rac1signaling axis. Our findings establish thatOstm1is an essential regulator of T cell ontogeny.Graphical abstractDisplay OmittedHighlights•Loss ofOstm1causes severe thymus hypocellularity•Ostm1is a modulator of the T cell differentiation program from the CLPs onwards•Targeted CD2-Ostm1in Ostm1 null mice leads to partial rescue of DN differentiation•Ostm1null DN1 transcriptome identifies aFoxo1-Klf2-S1pr1-Gnai1-Rac1signaling axisMolecular biology; Immunology; Cell biology
