MicroRNAs are small RNAs that bind and repress target mRNAs. The first microRNA was discovered by Victor Ambros and colleagues in Harvard’s Department of Cellular and Developmental Biology, the precursor to MCB. Today, microRNAs are thought to account for 1% to 3% of human genes. Computational analyses have suggested that more than 25% of all human genes are regulated by microRNAs and that individual microRNAs might each repress hundreds of specific target mRNAs. It has been unclear, however, whether microRNAs indeed have numerous targets in vivo and how they regulate these targets. Research by Antonio Giraldez, Alex Schier, and their collaborators now indicates that the microRNA miR-430 represses hundreds of mRNAs during early zebrafish embryogenesis by removing their poly(A) tail.
Giraldez et al. had previously identified miR-430 as a microRNA that is required for the normal morphogenesis of the zebrafish embryo. Without miR-430, embryos undergo abnormal gastrulation and brain development. To identify the target mRNAs for miR-430, the authors assumed that miR-430 induces the decay of its targets. Using microarrays, they isolated mRNAs that accumulate in the absence of miR-430. After computational analysis and in vivo target validation, the researchers found that miR-430 directly regulates several hundred mRNAs. Strikingly, the majority of these mRNAs are maternally expressed, that is, they are made by the mother and deposited into the egg. Such maternal mRNAs help to drive early embryogenesis, because the embryo itself is transcriptionally silent during this stage and zygotic transcription initiates only later. The researchers found that miR-430 is one of the first genes to be transcribed in the embryo and is required to accelerate the decay of many maternal mRNAs. Thus, miR-430 helps to rid the embryo of maternal mRNAs and promotes the transition from the maternal to the zygotic mode of development.
Giraldez et al. also studied the mechanism by which miR-430 regulates target mRNAs. They found that miR-430 blocked the translation and induced the decay of its targets. Strikingly, miR-430 also induced the deadenylation of mRNAs. Previous studies had shown that mRNAs need to be polyadenylated to be stabilized and efficiently translated. It is thus possible that the first step in miR-430 function is to deadenylate its target mRNAs, which results in translational repression and mRNA decay. This mechanism might resolve a long-standing conundrum in the microRNA field—some studies proposed that microRNAs block translation, whereas others suggested that microRNAs induce mRNA decay. MicroRNA-induced deadenylation could provide a common basis for these seemingly conflicting observations. Further studies are needed to determine if deadenylation is the primary mechanism for microRNA function.
Taken together, the research by Giraldez et al. suggests that miR-430 and other microRNAs facilitate the transition between developmental states by inducing the decay and deadenylation of hundreds of target mRNAs.
Three of the Distinguished Authors: