Abstract
MicroRNAs (miRNAs) have been found to regulate gene expression across eukaryotic species, but the function of most miRNA genes remains unknown. Here we describe how the analysis of the expression patterns of a well-conserved miRNA gene, mir-57, at cellular resolution for every minute during early development of Caenorhabditis elegans provided key insights in understanding its function. Remarkably, mir-57 expression shows strong positional bias but little tissue specificity, a pattern reminiscent of Hox gene function. Despite the minor defects produced by a loss of function mutation, overexpression of mir-57 causes dramatic posterior defects, which also mimic the phenotypes of mutant alleles of a posterior Hox gene, nob-1, an Abd homolog. More importantly, nob-1 expression is found in the same two posterior AB sublineages as those expressing mir-57 but with an earlier onset. Intriguingly, nob-1 functions as an activator for mir-57 expression; it is also a direct target of mir-57. In agreement with this, loss of mir-57 function partially rescues the nob-1 allele defects, indicating a negative feedback regulatory loop between the miRNA and Hox gene to provide positional cues. Given the conservation of the miRNA and Hox gene, the regulatory mechanism might be broadly used across species. The strategy used here to explore mir-57 function provides a path to dissect the regulatory relationship between genes.
Highlights
MiRNAs are small endogenous RNA molecules found in most eukaryotic species that are involved in post-transcriptional regulation of genes required for cell fate determination, metabolism and carcinogenesis among other processes [1]
Using live cell imaging and automated expression analysis, we found a miRNA gene, mir-57, is expressed in a position rather than tissue dependent way
By investigating interactions between genes of these classes expressed in mir-57 expressing cells, we demonstrated by both genetic analysis and gene expression assays that a negative feedback loop between a posterior Hox gene, nob-1, and mir-57 regulates posterior cell fate determination in C. elegans
Summary
MiRNAs are small endogenous RNA molecules found in most eukaryotic species that are involved in post-transcriptional regulation of genes required for cell fate determination, metabolism and carcinogenesis among other processes [1]. Over 155 miRNAs have been identified in C. elegans through a combination of molecular and bioinformatics methods [4,5,6,7,8] Many of these are well conserved across eukaryotes, but only a few have been functionally characterized. For example in C. elegans, the founding members of miRNAs lin-4 and let-7 [9,10] regulate lin-14 and hbl-1 respectively and are involved in controlling timing of development. The lys-6 and mir-273 miRNAs function sequentially and asymmetrically to control chemosensory neuronal development [11,12]. Mir-61 has been shown to be a direct transcriptional target of LIN-12, and is involved in down regulation of vav-1, which in turn promotes LIN-12 activity in presumptive 2u VPCs [13].
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