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LIN-14 is a nuclear protein that plays a crucial role in regulating developmental timing in the nematode worm Caenorhabditis elegans. It functions as a heterochronic gene, controlling the timing of developmental events during larval development. 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. LIN-14 is a BEN domain transcription factor, capable of binding DNA and directly regulating gene expression. 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.

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. These Lin-4 microRNAs bind to complementary sequences in the 3' untranslated region (UTR) of the Lin-14 mRNA, forming multiple RNA duplexes. 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).

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." Their work on the lin-4 microRNA and its regulation of the Lin-14 protein dates back to the late 1980s and early 1990s.

References

1. Hong Y, Lee RC, Ambros V (March 2000). "Structure and function analysis of LIN-14, a temporal regulator of postembryonic developmental events in Caenorhabditis elegans". Molecular and Cellular Biology. 20 (6): 2285–2295. doi:10.1128/MCB.20.6.2285-2295.2000. PMC 110844. PMID 10688674.
2. ^ Ambros 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. PMID 10889059.
3. Greene S, Huang J, Hamilton K, Tong L, Hobert O, Sun H (March 2023). "The heterochronic LIN-14 protein is a BEN domain transcription factor". Current Biology. 33 (6): R217 – R218. Bibcode:2023CBio...33R.217G. doi:10.1016/j.cub.2023.02.016. PMC 10080584. PMID 36977380.
4. Hristova M, Birse D, Hong Y, Ambros V (December 2005). "The Caenorhabditis elegans heterochronic regulator LIN-14 is a novel transcription factor that controls the developmental timing of transcription from the insulin/insulin-like growth factor gene ins-33 by direct DNA binding". Molecular and Cellular Biology. 25 (24): 11059–11072. doi:10.1128/MCB.25.24.11059-11072.2005. PMC 1316966. PMID 16314527.
5. ^ Lee 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. PMID 8252621.
6. ^ Wightman 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. PMID 8252622.
7. Shi Z, Hayes G, Ruvkun G (2013). "Dual regulation of the lin-14 target mRNA by the lin-4 miRNA". PLOS ONE. 8 (9): e75475. Bibcode:2013PLoSO...875475S. doi:10.1371/journal.pone.0075475. PMC 3772890. PMID 24058689.
8. "The Nobel Prize in Physiology or Medicine 2024". The Nobel Foundation. 10 October 2024.
9. Ambros V, Horvitz HR (June 1987). "The lin-14 locus of Caenorhabditis elegans controls the time of expression of specific postembryonic developmental events". Genes & Development. 1 (4): 398–414. doi:10.1101/gad.1.4.398. PMID 3678829.

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