Heterochronic genes regulate the timing of cell fate decisions. In C. elegans,
lin-41 mutant animals precociously express adult characteristics at earlier larval stages, while overexpression of
lin-41 causes some cells to reiterate late larval fates at the adult stage.
lin-41 negatively regulates the expression of
lin-29, a transcription factor required for adult fates, that appears to be translated at the L4 and adult stages from an mRNA expressed from the L2 stage. In a
lin-41 mutant, LIN-29 protein appears as early as the L2 stage. In the epidermis
lin-41 expression is down-regulated during the L4 stage, which is when expression of
lin-29 protein is observed. Thus LIN-41 may regulate the timing of
lin-29 mRNA translation or protein stability.
lin-41 is a divergent members of the RBCC (RING finger, B-Box, Coiled coil) family of regulatory proteins, that includes the RNA binding protein SSA/Ro, and the tumor suppressor genes PML, TIF1 and rpt. A fusion of GFP to a functional LIN-41 protein reveals that the protein is predominantly cytoplasmic. Based on precedents from the RBCC gene family, LIN-41 may regulate
lin-29 expression by binding to its mRNA to control its translation, or by binding to the LIN-29 protein to regulate its stability. We isolated
lin-41 mutations as suppressors of
let-7 mutations.
let-7 encodes a small untranslated RNA that is expressed just prior to the L4 stage and is complementary to two sites in the 3UTR of
lin-41. This complementarity and the temporal down-regulation of
lin-41 expression at the time when
let-7 RNA is up-regulated suggests that
let-7 inhibits
lin-41 expression by binding to its 3 UTR. Thus, activation of the
let-7 RNA during the L4 stage may down-regulate LIN-41 expression to then relieve the inhibition of
lin-29. The heterochronic genes
let-7,
lin-29 and
lin-41 are conserved (and expressed) in Drosophila and mammals (also see abstract by Reinhart et al). Moreover, the Drosophila
lin-41 homologue has a
let-7 complementary sequence in its 3'UTR, suggesting that the mechanism for regulating gene expression by small RNAs may be conserved across animal phylogeny.