Explicit genetic control of temporal patterning has been revealed by analysis of the heterochronic gene pathway in C. elegans. Depending on the mutation, stage-specific developmental events in heterochronic mutant animals occur at either earlier or later stages than they would normally. Two small regulatory RNAs control successive steps in this pathway by regulating the activities of key target mRNAs that encode cell fate determination factors. Both regulatory RNAs are complementary to these target heterochronic genes. In one case, this regulation has been shown to occur at a post-transcriptional step. We propose to discern the mechanism by which these regulatory RNAs control the translation of their mRNA targets. We will use a combination of genetic and biochemical techniques in this analysis. The discovery of two regulatory RNAs in the heterochronic pathway suggests the attractive model that the expression of a regulatory RNA at each larval molt may trigger the down-regulation of particular stage-specific regulatory proteins. Regulatory RNAs like lin-4 and let-7 may also be more general in animal species and may perform the same biochemical function in translational control. We have detected possible let-7 homologues in Drosophila and human genome databases, suggesting that its function may be more ancient than the common ancestor of molting animals. Noncoding RNAs in eukaryotic organisms are involved in translation (the ribosomal and tRNAs), RNA processing (the Un RNAs) and RNA methylation/pseudouridination (the snoRNAs). Regulatory RNAs such as let-7 tend to be missed by genome sequence analysis and this is a major problem for genomics. Our analysis of the key features of these regulatory RNAs, their promoter elements, the key loops and bulges for function, the regions complementary to target mRNAs, may enable the informatic detection of analogous but not homologous regulatory RNAs in genome databases.
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