Abstract
Abstract Transcriptional regulation has been shown to play a vital role in thymocyte development, however co-/post-transcriptional modifications are also important regulatory mechanisms for T cell development. Here, we demonstrate that loss of Mbnl1, a developmentally regulated alternative RNA processing factor, leads to dysregulation of thymocyte development. Mbnl1-/- mice develop thymic hyperplasia due to accumulation of CD4+CD8+ double positive thymocytes. Mbnl1-/- thymocytes are resistant to steroid-induced apoptosis in vitro and current studies are focused on characterizing Mbnl1-/- thymocyte proliferation defects as well as peripheral T cells in Mbnl1-/- mice. Whole thymic transcriptome comparisons between Mbnl1-/- and wild type mice indicate 476 mis-splicing events in >300 genes, including those involved in T cell receptor assembly and signaling. Additionally, 688 differentially expressed genes identified between wild type and Mbnl1-/- (FDR < 0.01) demonstrate enrichment for immune processes, such as lymphocyte activation and stimulus response. Since Mbnl1 regulates alternative splicing and polyadenylation during the postnatal period, this study suggests that fetal to adult RNA processing switches are critical for normal thymocyte development.
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