The zinc-finger protein SEA-2 regulates larval developmental timing and adult lifespan in C. elegans

National Institute of Biological Sciences, Beijing, 102206 Beijing, People's Republic of China.
Development (Impact Factor: 6.46). 04/2011; 138(10):2059-68. DOI: 10.1242/dev.057109
Source: PubMed


Like other biological processes, aging is regulated by genetic pathways. However, it remains largely unknown whether aging is determined by an innate programmed timing mechanism and, if so, how this timer is linked to the mechanisms that control developmental timing. Here, we demonstrate that sea-2, which encodes a zinc-finger protein, controls developmental timing in C. elegans larvae by regulating expression of the heterochronic gene lin-28 at the post-transcriptional level. lin-28 is also essential for the autosomal signal element (ASE) function of sea-2 in X:A signal assessment. We also show that sea-2 modulates aging in adulthood. Loss of function of sea-2 slows the aging process and extends the adult lifespan in a DAF-16/FOXO-dependent manner. Mutation of sea-2 promotes nuclear translocation of DAF-16 and subsequent activation of daf-16 targets. We further demonstrate that insulin/IGF-1 signaling functions in the larval heterochronic circuit. Loss of function of the insulin/IGF-1 receptor gene daf-2, which extends lifespan, also greatly enhances the retarded heterochronic defects in sea-2 mutants. Regulation of developmental timing by daf-2 requires daf-16 activity. Our study provides evidence for intricate interplay between the heterochronic circuit that controls developmental timing in larvae and the timing mechanism that modulates aging in adults.

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Available from: Xinxin Huang, Mar 25, 2014
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    • "Although several mechanisms have been identified that down-regulate lin-28 mRNA stability or translation, little is known about the mechanism that eliminates LIN-28 protein. Translation of LIN-28 is down-regulated by the lin-4 miRNA possibly in concert with SEA-2 (Huang et al., 2011, Moss et al., 1997, Seggerson et al., 2002). LIN-66, and DAF-12 regulate translation from the LIN-28 mRNA independently of lin-4 (Huang et al., 2011, Morita andHan, 2006). "
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    ABSTRACT: The heterochronic genes lin-28, let-7, and lin-41, regulate fundamental developmental transitions in animals, e.g. stemness vs. differentiation and juvenile vs. adult states. We identify a new heterochronic gene, lep-2, in Caenorhabditis elegans. Mutations in lep-2 cause a delay in the juvenile/adult transition, with adult males retaining pointed, juvenile tail tips, and displaying defective sexual behaviors. In both sexes, lep-2 mutants fail to cease molting or produce an adult cuticle. We find that lep-2 post-translationally regulates LIN-28 by promoting LIN-28 protein degradation. lep-2 is the sole C. elegans ortholog of the Makorin (Mkrn) family of proteins. Like lin-28 and other heterochronic pathway members, vertebrate Mkrns are involved in developmental switches, including the timing of pubertal onset in humans. Based on shared roles, conservation, and the interaction between lep-2 and lin-28 shown here, we propose that Mkrns-together with other heterochronic genes-constitute an anciently conserved module regulating switches in development.
    Full-text · Article · Jan 2016 · Development
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    • "We note, though, that sea-2 has roles in development beyond controlling sex determination and dosage compensation. Huang et al. (2011) demonstrated a role for sea-2 in regulating larval developmental timing and adult life span. "
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    ABSTRACT: Sex is determined in Caenorhabditis elegans by the ratio of X chromosomes to the sets of autosomes, the X:A signal. A set of genes called X signal elements (XSEs) communicates X-chromosome dose by repressing the masculinizing sex determination switch gene xol-1 (XO lethal) in a dose-dependent manner. xol-1 is active in 1X:2A embryos (males) but repressed in 2X:2A embryos (hermaphrodites). Here we showed that the autosome dose is communicated by a set of autosomal signal elements (ASEs) that act in a cumulative, dose-dependent manner to counter XSEs by stimulating xol-1 transcription. We identified new ASEs and explored the biochemical basis by which ASEs antagonize XSEs to determine sex. Multiple antagonistic molecular interactions carried out on a single promoter explain how different X:A values elicit different sexual fates. XSEs (nuclear receptors and homeodomain proteins) and ASEs (T-box and zinc finger proteins) bind directly to several sites on xol-1 to counteract each other's activities and thereby regulate xol-1 transcription. Disrupting ASE- and XSE-binding sites in vivo recapitulated the misregulation of xol-1 transcription caused by disrupting cognate signal element genes. XSE- and ASE-binding sites are distinct and nonoverlapping, suggesting that direct competition for xol-1 binding is not how XSEs counter ASEs. Instead, XSEs likely antagonize ASEs by recruiting cofactors with reciprocal activities that induce opposite transcriptional states. Most ASE- and XSE-binding sites overlap xol-1's -1 nucleosome, which carries activating chromatin marks only when xol-1 is turned on. Coactivators and corepressors tethered by proteins similar to ASEs and XSEs are known to deposit and remove such marks. The concept of a sex signal comprising competing XSEs and ASEs arose as a theory for fruit flies a century ago. Ironically, while the recent work of others showed that the fly sex signal does not fit this simple paradigm, our work shows that the worm signal does.
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