The <em>mir-51</em> Family of microRNAs Functions in Diverse Regulatory Pathways in <em>Caenorhabditis elegans</em>

<div><p>The <em>mir-51</em> family of microRNAs (miRNAs) in <em>C. elegans</em> are part of the deeply conserved miR-99/100 family. While loss of all six family members (<em>mir-51-56)</em> in <em>C. elegans</em> results in embryonic lethality, loss of individual <em>mir-51</em> family members results in a suppression of retarded developmental timing defects associated with the loss of <em>alg-1</em>. The mechanism of this suppression of developmental timing defects is unknown. To address this, we characterized the function of the <em>mir-51</em> family in the developmental timing pathway. We performed genetic analysis and determined that <em>mir-51</em> family members regulate the developmental timing pathway in the L2 stage upstream of <em>hbl-1</em>. Loss of the <em>mir-51</em> family member, <em>mir-52</em>, suppressed retarded developmental timing defects associated with the loss of <em>let-7</em> family members and <em>lin-46</em>. Enhancement of precocious defects was observed for mutations in <em>lin-14, hbl-1,</em> and <em>mir-48(ve33)</em>, but not later acting developmental timing genes. Interestingly, <em>mir-51</em> family members showed genetic interactions with additional miRNA-regulated pathways, which are regulated by the <em>let-7</em> and <em>mir-35</em> family miRNAs, lsy-6, miR-240/786, and miR-1. Loss of <em>mir-52</em> likely does not suppress miRNA-regulated pathways through an increase in miRNA biogenesis or miRNA activity. We found no increase in the levels of four mature miRNAs, let-7, miR-58, miR-62 or miR-244, in <em>mir-52</em> or <em>mir-52/53/54/55/56</em> mutant worms. In addition, we observed no increase in the activity of ectopic lsy-6 in the repression of a downstream target in uterine cells in worms that lack <em>mir-52</em>. We propose that the <em>mir-51</em> family functions broadly through the regulation of multiple targets, which have not yet been identified, in diverse regulatory pathways in <em>C. elegans</em>.</p>