Lessons from microRNA mutants in worms, flies and mice.

It is apparent that microRNAs (miRNAs) are important components in the regulation of genetic networks in many biological contexts. Based on computational analysis, typical miRNAs are inferred to have tens to hundreds of conserved targets. Many miRNA-target interactions have been validated by various means, including heterologous tests in cultured cells and gain-of-function approaches that can yield striking phenotypes in whole animals. However, these strategies do not report on the endogenous importance of such miRNA activities. Likewise, studies of miRNA pathway mutants can suggest an endogenous role for miRNAs in a given setting, but do not identify roles for specific miRNAs. Therefore, these approaches must be complemented with the analysis of miRNA mutant alleles. In this review, we describe some of the lessons learned from studying miRNA gene deletions in worms, flies and mice, and discuss their implications for the control of endogenous regulatory networks.