T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer

Abstract

The ribonuclease III enzyme Dicer is essential for the processing of micro-RNAs (miRNAs) and small interfering RNAs (siRNAs) from double-stranded RNA precursors. miRNAs and siRNAs regulate chromatin structure, gene transcription, mRNA stability, and translation in a wide range of organisms. To provide a model system to explore the role of Dicer-generated RNAs in the differentiation of mammalian cells in vivo, we have generated a conditional Dicer allele. Deletion of Dicer at an early stage of T cell development compromised the survival of αβ lineage cells, whereas the numbers of γδ-expressing thymocytes were not affected. In developing thymocytes, Dicer was not required for the maintenance of transcriptional silencing at pericentromeric satellite sequences (constitutive heterochromatin), the maintenance of DNA methylation and X chromosome inactivation in female cells (facultative heterochromatin), and the stable shutdown of a developmentally regulated gene (developmentally regulated gene silencing). Most remarkably, given that one third of mammalian mRNAs are putative miRNA targets, Dicer seems to be dispensable for CD4/8 lineage commitment, a process in which epigenetic regulation of lineage choice has been well documented. Thus, although Dicer seems to be critical for the development of the early embryo, it may have limited impact on the implementation of some lineage-specific gene expression programs.

The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome

“…2 Using the conditional deletion of Dicer or Argonaute 2, two key enzymes that control the production of mature miRNAs, the importance of miRNAs in the development of the immune system and the regulation of immune responses was discovered. 3,4 Several miRNAs have been found to be involved in the activation, differentiation and function of immune cells by affecting key transcripts. 5 The aberrant expression of miRNAs in some inflammatory diseases has also been investigated.…”

Dicer-Dependent MicroRNA Pathway Controls Invariant NKT Cell Development

“…miRNAs regulate basic functions such as proliferation, apoptosis, lineage commitment, or differentiation of cells that constitute different tissues and organs, including the immune system (9, 10). Conditional deletion of Dicer provided insight into the role of miRNAs in controlling the development of B and T lymphocytes (11)(12)(13)(14)(15)(16). Dicer deletion early in T cell development (DN stage) caused a 10-fold decrease in DP and single-positive (SP) thymocyte numbers, though the CD4/CD8 lineage choice was unaffected (13).…”

“…Conditional deletion of Dicer provided insight into the role of miRNAs in controlling the development of B and T lymphocytes (11)(12)(13)(14)(15)(16). Dicer deletion early in T cell development (DN stage) caused a 10-fold decrease in DP and single-positive (SP) thymocyte numbers, though the CD4/CD8 lineage choice was unaffected (13). Dicer deletion at later stage of T cell development (DP stage) did not alter number and composition of mainstream thymocytes, though it resulted in a substantial reduction in thymic CD4 ϩ CD25 ϩ Foxp3 ϩ natural regulatory T (Treg) cells (14,17).…”

“…Dicer lox/lox , cd4Dicer ⌬/⌬ , and lckDicer ⌬/⌬ transgenic mice were described (13,14). Dicer lox/lox were crossed with both hCD2Cre and R26R-EYFP transgenic mice (18) to delete one (cd2Dicer ⌬/wt ) or both (cd2Dicer ⌬/⌬ ) Dicer lox alleles expressing EYFP upon deletion of a floxed transcriptional stop cassette inserted into the rosa26 locus.…”

NKp46‐mediated Dicer1 inactivation results in defective NK‐cell differentiation and effector functions in mice

“…Moreover, in both studies, the extent of Dicer1 deletion was limited and as much as 50% of the initial microRNA quantity was still present. To clarify the role of Dicer1 in NK cells, we generated a model of NK-specific Dicer1 deletion by crossing Dicer1 lox/lox mice [9] with Ncr1 iCre mice expressing the improved Cre recombinase under the dependence of the Ncr1 promoter [22]. …”