LIN-14 is a nuclear protein that plays a crucial role in regulating developmental timing in the nematode worm Caenorhabditis elegans.[1][2] It functions as a heterochronic gene, controlling the timing of developmental events during larval development.[2] LIN-14 protein levels are high at the beginning of the first larval stage (L1) and then rapidly decline, which is essential for the transition from early to late cell fates.[2] LIN-14 is a BEN domain transcription factor, capable of binding DNA and directly regulating gene expression.[3] The protein's activity is tightly regulated by lin-4, a microRNA which inhibits LIN-14 protein synthesis through complementary base pairing with sequences in the lin-14 mRNA 3' untranslated region.[4]
Regulation
The expression of the Lin-14 gene in Caenorhabditis elegans is tightly regulated by the Lin-4 gene through a microRNA-mediated mechanism. Lin-4 produces small RNAs that act as negative regulators of Lin-14 protein synthesis.[5] These Lin-4 microRNAs bind to complementary sequences in the 3' untranslated region (UTR) of the Lin-14 mRNA, forming multiple RNA duplexes.[6] This interaction leads to a post-transcriptional regulation of Lin-14 translation, resulting in a decrease over time of LIN-14 protein levels starting in the first larval stage (L1).[5][7]
Nobel Prize
This work on microRNA-mediated gene regulation, including the discovery of the Lin-4/Lin-14 regulatory mechanism, was recognized with the 2024 Nobel Prize in Physiology or Medicine, awarded to Victor Ambros and Gary Ruvkun "...for the discovery of microRNA and its role in post-transcriptional gene regulation."[8] Their work on the lin-4 microRNA and its regulation of the Lin-14 protein dates back to the late 1980s and early 1990s.[9][6]
^ abcAmbros V (August 2000). "Control of developmental timing in Caenorhabditis elegans". Current Opinion in Genetics & Development. 10 (4): 428–433. doi:10.1016/s0959-437x(00)00108-8. PMID10889059.
^ abLee RC, Feinbaum RL, Ambros V (December 1993). "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14". Cell. 75 (5): 843–54. doi:10.1016/0092-8674(93)90529-y. PMID8252621.
^ abWightman B, Ha I, Ruvkun G (December 1993). "Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans". Cell. 75 (5): 855–62. doi:10.1016/0092-8674(93)90530-4. PMID8252622.