▲ FIGURE 22-10 Timing of specific types of cell division during development of C. elegans. (a) The pattern of cell division for the V5 cell of C. elegans is shown for normal worms and for a heterochronic mutant called lin-14. In the lin-14 mutant, the pattern of cell division (red arrows) that normally occurs only in the second larval stage (L2) occurs in the first larval stage (L1), causing the PDNB neuroblast to be generated prematurely. In the mutant, the V5 cell behaves during L1 like cell "X" (purple) normally does in L2. The inference is that the LIN-14 protein prevents L2-type cell divisions, although precisely how it does so is unknown. (b) Two small regulatory RNAs, lin-4 and let-7, serve as coordinating timers of gene expression. Binding of the lin-4

be defective in heterochronic worm mutants encode RNA-binding or DNA-binding proteins, which presumably coordinate expression of other genes. However, two other genes (lin-4 and let-7) involved in regulating the timing of cell divisions were initially extremely puzzling, as they appeared to encode small RNAs that do not encode any protein. To discover the products of these genes, scientists first determined which pieces of genomic DNA could restore gene function, and therefore proper cell lineage, to mutants defective in each gene. They then did the same thing with genomic DNA from the corresponding genomic regions of different species of worm. Comparison of the "rescuing" fragments from the different species revealed that they shared common short sequences with little protein-coding potential.

The short RNA molecules encoded by lin-4 and let-7 were subsequently shown to inhibit translation of the mRNAs encoded by lin-14 and other heterochronic genes (Figure 22-10b). These small RNAs, or micro RNAs (miRNAs), are complementary to sequences in the 3' untranslated parts of target mRNAs and are believed to control translation of the mRNAs by hy-

RNA to the 3' untranslated regions (UTRs) of lin-14 and lin-28 mRNAs prevents translation of these mRNAs into protein. This occurs following the first larval (L1) stage, permitting development to proceed to the later larval stages. Starting in the fourth larval stage (L4), production of let-7 RNA begins. It hybridizes to lin-14, lin-28, and lin-41 mRNAs, preventing their translation. LIN-41 protein is an inhibitor of translation of the lin-29 mRNA, so the appearance of let-7 RNA allows production of LIN-29 protein, which is needed for generation of adult cell lineages. LIN-4 may also bind to lin-41 RNA at later stages. Only the 3' UTRs of the mRNAs are depicted. [Adapted from B. J. Reinhart et al., 2000, Nature 403:901.]

bridizing them. Temporal changes in the production of these and other miRNAs during the life cycle of C. elegans serve as a regulatory clock for cell lineage. Molecules related to let-7 RNA have been identified in many other animals including vertebrates and insects; since their production is temporally regulated in these animals as well, they may serve a similar function in their development as in C. elegans. How production of these regulatory miRNAs is temporally controlled is not yet known, but they have turned out to play many roles in regulating gene expression (Chapter 12).

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