Disease relevance of lin-28

• The mammalian ortholog of C. elegans lin-28, which is downregulated by lin-4 in worms via 3' untranslated region binding, was also repressed during neuronal differentiation of mammalian embryonal carcinoma cells [1].

High impact information on lin-28

• Furthermore, lin-14 and lin-28 are targets of the lin-4 miRNA, and we show that the mRNA levels for these protein-coding genes significantly decrease in response to lin-4 expression [2].
• Deleting the LCE produces a dominant gain-of-function allele that causes a retarded phenotype, indicating that lin-28 activity is a switch that controls choices of stage-specific fates [3].
• Mutations in the heterochronic gene lin-28 of C. elegans cause precocious development where diverse events specific to the second larval stage are skipped. lin-28 encodes a cytoplasmic protein with a cold shock domain and retroviral-type (CCHC) zinc finger motifs, consistent with a role for LIN-28 in posttranscriptional regulation [3].
• The phenotypes of multiply mutant strains suggest a model wherein the L/A switch is controlled by the stage-specific activity of a regulatory hierarchy: At early stages of wild-type development, lin-14 and lin-28 inhibit lin-29 and thus prevent switching [4].
• Our results further suggest that dauer larva morphogenesis by hypodermal cells requires that lin-28 acts to inhibit lin-29 during early larval stages [5].

Biological context of lin-28

• These results suggest that lin-28 expression is regulated by multiple independent mechanisms including LIN-14-mediated upregulation of mRNA level, miRNAs-mediated RNA degradation, LIN-66-mediated translational inhibition and DAF-12-involved translation promotion [6].
• The timing of postembryonic developmental programs in Caenorhabditis elegans is regulated by a set of so-called heterochronic genes, including lin-28 that specifies second larval programs. lin-66 mutations described herein cause delays in vulval and seam cell differentiation, indicating a role for lin-66 in timing regulation [6].
• Heterochronic genes control the timing of vulval development in the C. elegans hermaphrodite. lin-14 or lin-28 loss-of-function mutations cause the vulval precursor cells (VPCs) to enter S phase and to divide one larval stage earlier than in the wild type [7].
• Therefore, the lin-4-independent circuit likely contributes substantially to the down-regulation of lin-28 that occurs during normal development [8].
• Mammalian lin-28 messenger RNAs contain conserved predicted binding sites in their 3' untranslated regions for neuron-expressed miR-125b (a lin-4 ortholog), let-7a, and miR-218 [1].

Anatomical context of lin-28

• In lin-28 mutants, vulva development is similar to wild-type vulva development except that it occurs precociously, in the second larval stage (L2) [9].

Other interactions of lin-28

• A second regulatory RNA, lin-4, negatively regulates lin-14 and lin-28 through RNA-RNA interactions with their 3' untranslated regions [10].
• We report that a stage-specific developmental program, dauer larva formation, is temporally regulated by four heterochronic genes, lin-4, lin-14, lin-28, and lin-29 [5].
• Our analysis indicates that lin-46 acts at a step immediately downstream of lin-28, affecting both the regulation of the heterochronic gene pathway and execution of stage-specific developmental events at two stages: the third larval stage and adult [11].
• In these mutants, somatic cells repeat L2-specific cellular programs of division and migration at the L3 stage; epistasis experiments place daf-12 between lin-14 and lin-28 within the heterochronic pathway [12].

References