Dicer in immune cell development and function

Abstract

Dicer is an enzyme of the RNase III endoribonuclease family, which is crucial for RNA interference (RNAi) in eukaryotes. Dicer is a component of the protein machinery (the RNA Induced Silencing Complex [RISC]) which is involved in catalyzing the formation of mature microRNAs from their precursors in the process of microRNA biogenesis. RISC-associated microRNAs bind to specific sequences in the 3' untranslated region of cognate mRNAs largely through complementary base pairing, resulting in either translational inhibition and/or the degradation of a specific mRNA pool. MicroRNAs epigenetically regulate the cellular levels of receptors, transcription factors and signaling proteins that govern the developmental pathways and functions of multiple cellular processes. The pivotal role played by Dicer in microRNA formation has also piqued the interest of molecular immunologists who have sought to understand the biological relevance of microRNAs in the development and function of the immune system. Here, we review the major findings of these studies and provide an overview of the role of Dicer and microRNAs in immune cell development and function. Additionally, we highlight deficiencies in our knowledge and new research areas that may enhance our understanding of the role of Dicer and microRNAs in immunity.

Figure 1

Cre-lox technique for the conditional deletion of dicer1. In this method, a Cre mouse is generated (parent 1) wherein the gene that codes for the Cre recombinase enzyme is positioned downstream of a Transcription Factor Binding Site (TFBS). A TFBS is carefully chosen such that it recruits a transcription factor that is specifically expressed in a unique cellular subset or at a precise developmental stage. This allows the Cre recombinase to be expressed only when the transcription factor is available. A floxed mouse is also generated (parent 2) wherein the gene (or segement of a gene) targeted for deletion, which in this example is exon 23 of dicer1, is flanked by LoxP sites. This construct also contains a reporter gene, as indicated in the figure. A Cre LoxP mouse is obtained when the Cre mouse is crosses with the Floxed mouse. In a Cre LoxP mouse, the Cre recombinase, when expressed exclusively in cells where the specific transcription factor is available, drives homologous recombination between the loxP sites, leading to the deletion of exon 23 of dicer1 and allows the reporter gene to be expressed. Moreover, in cells that do not contain the specific transcription factor, the dicer1 gene will not be disrupted. TSS: Transcription Start Site, STOP: Stop codon.