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[
Mech Ageing Dev,
2007]
Technological advancements in invertebrate model organisms have recently made it possible to survey many or all of the genes in the genome for phenotypes of interest. In both C. elegans and S. cerevisiae, genome-wide searches for hypomorphic mutations that extend life span have been performed. The results from these screens are starting to provide a more complete view of the range of life span determinants in eukaryotes. In addition, it is becoming possible to test the premise that conserved aging genes and pathways regulate aging in disparate eukaryotic species. Here we compare and contrast the results from genome-wide aging screens and assess the likelihood that there are "public" aging mechanisms.
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[
Ann N Y Acad Sci,
2009]
Obligate aerobes, by definition, require oxygen in order to sustain life. Therefore, changes in environment or physiology that cause metabolic demand for oxygen to exceed supply (hypoxia) can be highly detrimental. Despite considerable variation in physiology and habitat between species, a majority of metazoa employ homologues of the hypoxia-inducible factor (HIF) transcription factors to adapt to oxygen deprivation. Studies in mammals, Drosophila and C. elegans have shown that regulation of HIF-alpha by prolyl hydroxylase (PHD)-mediated proteasomal degradation is conserved, as are a number of HIF target genes. More recently, analysis of coral and beetle HIFs has revealed that, unlike flies and worms, the C-terminal transactivation domain of HIF-alpha and its regulatory hydroxylase FIH-1 are also preserved. The reasons for variable conservation of this system are unknown. However, discovery of the "intermediary" properties of the beetle HIF pathway may prove a useful tool to better define HIF signaling in both mammals and invertebrates.
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[
Curr Opin Genet Dev,
1998]
Maternal factors laid down in the oocyte regulate blastomere identities in the early Caenorhabditis elegans embryo by activating zygotic patterning genes and restricting their expression to the appropriate lineages. A number of early-acting zygotic genes that specify various cell fates have been identified recently and their temporal and spatial regulation by maternal factors has begun to be elucidated.
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[
J Cell Sci,
2012]
MicroRNAs (miRNAs) are a class of short non-coding RNAs that bind mRNAs through partial base-pair complementarity with their target genes, resulting in post-transcriptional repression of gene expression. The role of miRNAs in controlling aging processes has been uncovered recently with the discovery of miRNAs that regulate lifespan in the nematode Caenorhabditis elegans through insulin and insulin-like growth factor-1 signaling and DNA damage checkpoint factors. Furthermore, numerous miRNAs are differentially expressed during aging in C. elegans, but the specific functions of many of these miRNAs are still unknown. Recently, various miRNAs have been identified that are up- or down-regulated during mammalian aging by comparing their tissue-specific expression in younger and older mice. In addition, many miRNAs have been implicated in governing senescence in a variety of human cell lines, and the precise functions of some of these miRNAs in regulating cellular senescence have helped to elucidate mechanisms underlying aging. In this Commentary, we review the various regulatory roles of miRNAs during aging processes. We highlight how certain miRNAs can regulate aging on the level of organism lifespan, tissue aging or cellular senescence. Finally, we discuss future approaches that might be used to investigate the mechanisms by which miRNAs govern aging processes.
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Semin Cell Dev Biol,
2022]
The nervous system emerges from a series of genetic programs that generate a remarkable array of neuronal cell types. Each cell type must acquire a distinct anatomical position, morphology, and function, enabling the generation of specialized circuits that drive animal behavior. How are these diverse cell types and circuits patterned along the anterior-posterior (A-P) axis of the animal body? Hox genes encode transcription factors that regulate cell fate and patterning events along the A-P axis of the nervous system. While most of our understanding of Hox-mediated control of neuronal development stems from studies in segmented animals like flies, mice, and zebrafish, important new themes are emerging from work in a non-segmented animal: the nematode Caenorhabditis elegans. Studies in C. elegans support the idea that Hox genes are needed continuously and across different life stages in the nervous system; they are not only required in dividing progenitor cells, but also in post-mitotic neurons during development and adult life. In C. elegans embryos and young larvae, Hox genes control progenitor cell specification, cell survival, and neuronal migration, consistent with their neural patterning roles in other animals. In late larvae and adults, C. elegans Hox genes control neuron type-specific identity features critical for neuronal function, thereby extending the Hox functional repertoire beyond early patterning. Here, we provide a comprehensive review of Hox studies in the C. elegans nervous system. To relate to readers outside the C. elegans community, we highlight conserved roles of Hox genes in patterning the nervous system of invertebrate and vertebrate animals. We end by calling attention to new functions in adult post-mitotic neurons for these paradigmatic regulators of cell fate.
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[
Crit Rev Biochem Mol Biol,
2012]
The CCAAT box promoter element and NF-Y, the transcription factor (TF) that binds to it, were among the first cis-elements and trans-acting factors identified; their interplay is required for transcriptional activation of a sizeable number of eukaryotic genes. NF-Y consists of three evolutionarily conserved subunits: a dimer of NF-YB and NF-YC which closely resembles a histone, and the "innovative" NF-YA. In this review, we will provide an update on the functional and biological features that make NF-Y a fundamental link between chromatin and transcription. The last 25 years have witnessed a spectacular increase in our knowledge of how genes are regulated: from the identification of cis-acting sequences in promoters and enhancers, and the biochemical characterization of the corresponding TFs, to the merging of chromatin studies with the investigation of enzymatic machines that regulate epigenetic states. Originally identified and studied in yeast and mammals, NF-Y - also termed CBF and CP1 - is composed of three subunits, NF-YA, NF-YB and NF-YC. The complex recognizes the CCAAT pentanucleotide and specific flanking nucleotides with high specificity (Dorn et al., 1997; Hatamochi et al., 1988; Hooft van Huijsduijnen et al, 1987; Kim & Sheffery, 1990). A compelling set of bioinformatics studies clarified that the NF-Y preferred binding site is one of the most frequent promoter elements (Suzuki et al., 2001, 2004; Elkon et al., 2003; Marino-Ramirez et al., 2004; FitzGerald et al., 2004; Linhart et al., 2005; Zhu et al., 2005; Lee et al., 2007; Abnizova et al., 2007; Grskovic et al., 2007; Halperin et al., 2009; Hakkinen et al., 2011). The same consensus, as determined by mutagenesis and SELEX studies (Bi et al., 1997), was also retrieved in ChIP-on-chip analysis (Testa et al., 2005; Ceribelli et al., 2006; Ceribelli et al., 2008; Reed et al., 2008). Additional structural features of the CCAAT box - position, orientation, presence of multiple Transcriptional Start Sites - were previously reviewed (Dolfini et al., 2009) and will not be considered in detail here.
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[
1983]
In 1974, Sydney Brenner published an elegant paper that described the genetic system of Caenorhabditis elegans and led to its use in research on a wide variety of topics, including aging (Brenner, 1974). Its small size (1mm as an adult) and determinate cell lineage has allowed a description of the entire somatic cell lineage from the one-cell stage to the adult (Sulston and Horvitz, 1977; Deppe et al., 1978; Kimble and Hirsh, 1979; Suslton et al., personal communication). Its ease of culture makes it an organism of choice for studies of various aspects of anatomy and physiology, including muscle formation and function (Zengel and Epstein, 1980; Mackenzie and Epstein, 1980), cuticle formation (Cox et al, 1981), neuroanatomy (Ward et al, 1975; Ware et al, 1975; Sulston et al, 1975), and behavior (Dusenbery, 1980). Several genes have been cloned by recombinant DNA techniques ablation (Kimble, 1981; Laufer and von Ehrenstin, 1981) procedures, as well as most of the modern molecular techniques, are in use.
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[
Cell,
1997]
The demonstrations in two papers in this issue of Cell (Rocheleau et al., 1997; Thorpe et al., 1997) of the involvement of a Wnt pathway in very early embryogenesis in Caenorhabditis elegans provides another significant step toward the ambitious but realistic goal of understanding all the basic strategies used to control embryogenesis in this model organism. At the same time, they challenge some of the prevailing models of Wnt signaling, suggesting that interactions among Wnt pathway components may vary in different developmental processes. With these papers, as well as the earlier reports on Wnt pathway genes
lin-44,
lin-17, and
pop-1 (Herman et al., 1995; Lin et al., 1995; Harris et al., 1996; Sawa et al., 1996) and new studies on Wnt pahtway genes reported in recent meetings, worm breeders have become a significant force in the army of Wnt researchers. They have also illustrated how different systems can provide important new complementary insights.
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Front Cell Dev Biol,
2020]
Stem cell development depends on post-transcriptional regulation mediated by RNA-binding proteins (RBPs) (Zhang et al., 1997; Forbes and Lehmann, 1998; Okano et al., 2005; Ratti et al., 2006; Kwon et al., 2013). Pumilio and FBF (PUF) family RBPs are highly conserved post-transcriptional regulators that are critical for stem cell maintenance (Wickens et al., 2002; Quenault et al., 2011). The RNA-binding domains of PUF proteins recognize a family of related sequence motifs in the target mRNAs, yet individual PUF proteins have clearly distinct biological functions (Lu et al., 2009; Wang et al., 2018). The <i>C. elegans</i> germline is a simple and powerful model system for analyzing regulation of stem cell development. Studies in <i>C. elegans</i> uncovered specific physiological roles for PUFs expressed in the germline stem cells ranging from control of proliferation and differentiation to regulation of the sperm/oocyte decision. Importantly, recent studies started to illuminate the mechanisms behind PUF functional divergence. This review summarizes the many roles of PUF-8, FBF-1, and FBF-2 in germline stem and progenitor cells (SPCs) and discusses the factors accounting for their distinct biological functions. PUF proteins are conserved in evolution, and insights into PUF-mediated regulation provided by the <i>C. elegans</i> model system are likely relevant for other organisms.
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[
Cell,
2004]
Heterotrimeric G proteins are well known for their function in signal transduction downstream of seven transmembrane receptors. More recently, however, genetic analysis in C. elegans and in Drosophila has revealed a second, essential function of these molecules in positioning the mitotic spindle and attaching microtubules to the cell cortex. Five new publications in Cell (Afshar et al., 2004; Du and Macara, 2004 [this issue of Cell]; Hess et al., 2004), Developmental Cell (Martin-McCaffrey et al., 2004), and Current Biology (Couwenbergs et al., 2004) show that this function is conserved in vertebrates and-like the classical pathway- involves cycling of G proteins between GDP and GTP bound conformations.