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nhl-2 Modulates MicroRNA Activity in Caenorhabditis elegans

Christopher M. Hammell, Isabella Lubin, Peter R. Boag, T. Keith Blackwell, and Victor Ambros

Cell 136 (5): 926–938, March 2009.
doi:10.1016/j.cell.2009.01.053

This week’s careful summary and analysis by Joel Neilson:

Lin-41 is a founding member of the heterochronic pathway and a member of the TRIM-NHL family of proteins.  The phenotype of the lin-41 loss- of-function is precocious development, but is not fully penetrant.  The authors were examining whether this phenotype could be accentuated by crossing in additional mutant alleles for other TRIM-NHL family  members.  In contrast to the accentuated phenotype they were expecting, they found that one of these loss-of-function mutants,  nhl-2, resulted in a mildly retarded heterochronic phenotype and rescued the defects in the lin-41 mutant.

To briefly summarize this study in the wrong order and a completely oversimplified manner, they then demonstrate that:

(1)  loss of nhl-2 gene function enhances the phenotype of individually non-penetrant LOF alleles for miRNAs in the let-7 family

(2)  loss of nhl-2 gene function enhances the phenotype of a weak LOF allele of a miRNA in a second family (lsy-6)

(3)  loss of nhl-2 gene function offsets phenotypes observed in animals ectopically expressing a let-7 family member

(4)  loss of nhl-2 gene function accentuates heterochronic defects in worms with mutations in core miRNA machinery components

(5)  all of this happens without modulation of the levels of mature miRNAs and is through previously characterized miRNA targets

(6)  NHL2 exhibits broad temporal-spatial expression

(7)  NHL2 co-localizes with and in fact touches CGH1.  They also genetically interact.

(8)  NHL-2 and CGH-1 physically interact with the core miRNA machinery in an
RNA-dependent fashion

(9)  CGH-1 still interacts with the core miRNA machinery in nhl-2 mutants.

This is a one of the best papers I have chosen for this forum and I got particularly excited upon reading the following in the introduction: “Current models do not adequately account for the facts that some miRNA targets appear to be regulated primarily at a translational level while others are regulated by mRNA turnover, or that a particular miRNA can have dramatically different potencies on distinct miRNA target reporters (Eulalio et al., 2007) therefore, it is likely that additional proteins can interact with miRISC to modulate the nature and efficacy of miRISC activity.”  Looking at the last clause of that sentence, they did in fact demonstrate that additional factors can modulate miRISC activity.  But that’s not what I got excited about in reading the introduction. To really nail down  the parts that current models do not adequately account for, someone really does need to show that a defined target, which sometimes (in a spatial or temporal manner) is affected one way by miRNA/RISC recognition. . .say, translational repression. . . and sometimes is  affected another way. . .say, deadenylation. . .by the same miRNA/RISC, and show what dictates this specificity.  This study did not directly address this issue but is definitely moving us in the right direction.