Judith Kimble et al. (2005) WormBook "Germline proliferation and its control."

Sarah L. Crittenden, Judith Kimble

[WormBook, 2005]

The C. elegans germ line proliferates from one primordial germ cell (PGC) set aside in the early embryo to over a thousand cells in the adult. Most germline proliferation is controlled by the somatic distal tip cell, which provides a stem cell niche at the distal end of the adult gonad. The distal tip cell signals to the germ line via the Notch signaling pathway, which in turn controls a network of RNA regulators. The FBF-1 and FBF-2 RNA-binding proteins promote continued mitoses in germ cells located close to the distal tip cell, while the GLD-1 , GLD-2 , GLD-3 , and NOS-3 RNA regulators promote entry into meiosis as germ cells leave the stem cell niche. In addition to these key regulators, many other genes affect germline proliferation.

Thomas C. Evans (2005) WormBook "Translational control of maternal RNAs."

Thomas C. Evans

[WormBook, 2005]

Early development of many species depends on the temporal and spatial control of maternal gene products. This review discusses the control of maternal mRNAs that encode regulators of C. elegans embryogenesis. In the C. elegans embryo, maternal mRNA regulation is crucial to the patterning of early cell fates. Translational control of key mRNAs spatially organizes cell signaling pathways, localizes transcription factor activities, and controls germ cell precursor development. From the few mRNAs studied thus far, some themes are beginning to emerge. Control of maternal mRNA translation begins in the hermaphrodite germ line. Distinct regulatory systems keep mRNAs silent during different stages of oogenesis, and lead to precise temporal and spatial patterns of translation in the embryo. In the embryo, cell polarity factors control the localization of translational regulators. Each maternal mRNA contains multiple elements in its 3'' untranslated region (3'' UTR) that specify the timing and localization of translation. A relatively small number of RNA-binding proteins likely control many mRNAs through these 3'' UTR elements. Therefore, the combination of RNA elements and the regulatory complexes recruited to them specify unique patterns of translation for different mRNAs. The mechanisms of translational control are only beginning to be explored, but are likely to regulate diverse developmental and cellular events in metazoans.

Jonathan Pettitt (2005) WormBook "The cadherin superfamily."

Jonathan Pettitt

[WormBook, 2005]

The cadherins are a major class of membrane proteins with prominent roles in cell adhesion, and the regulation of tissue organisation and morphogenesis. The C. elegans genome encodes 13 cadherins, including representatives of the major cadherin sub-types that are conserved between insects and vertebrates: the so-called classic, Fat-like, Flamingo and calsyntenin classes. The function of most of these in C. elegans is still unknown, or poorly understood, mainly because clear loss-of-function mutations have been isolated for only a few. As is true for the cadherin families of other organisms, most is known about classic cadherin function. C. elegans has a single classic cadherin gene, which encodes two isoforms: one predominantly expressed in the nervous system, and the other more broadly expressed in all epithelial cells. The epithelial cadherin-catenin complex appears to be functionally equivalent to that found in Drosophila and vertebrates, and is critically required for embryonic morphogenesis. Mutant phenotypes have also been described for cdh-3 and fmi-1 , which encode a Fat-like cadherin, and the C. elegans Flamingo homologue, respectively. cdh-3 mutants display incompletely penetrant defects in the morphogenesis of hyp10, the cell which forms the tip of the tail, and the excretory duct cell; though the mechanistic role of CDH-3 in these processes is not known. FMI-1 is required during neuronal development consistent with the known role of the Drosophila homologue in controlling tissue polarity. Five of the cadherins have no obvious homologues beyond the nematodes, and thus may be phyla-specific.

Barbara Conradt (2005) WormBook "Programmed cell death."

BARBARA CONRADT

[WormBook, 2005]

Programmed cell death is an integral component of C. elegans development. Genetic studies in C. elegans have led to the identification of more than two dozen genes that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular and biochemical studies have revealed the underlying conserved mechanisms that control these three phases of programmed cell death. In particular, an interplay of transcriptional regulatory cascades and networks involving CES-1 , CES-2 , HLH-1 / HLH-2 , TRA-1 , and other transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 in cells destined to die. A protein interaction cascade involving EGL-1 , CED-9 , CED-4 and CED-3 results in the activation of the key cell death protease CED-3 . The activation of CED-3 initiates the cell disassembly process and nuclear DNA fragmentation, which is mediated by the release of apoptogenic mitochondrial factors ( CPS-6 and WAH-1 ) and which involves multiple endo- and exo-nucleases such as NUC-1 and seven CRN nucleases. The recognition and removal of the dying cell is mediated by two partially redundant signaling pathways involving CED-1 , CED-6 and CED-7 in one pathway and CED-2 , CED-5 , CED-10 , CED-12 and PSR-1 in the other pathway. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in multicellular organisms.

Jonathan Hodgkin (2005) WormBook "Karyotype, ploidy, and gene dosage."

Jonathan Hodgkin

[WormBook, 2005]

The normal karyotype of Caenorhabditis elegans, with its five pairs of autosomes and single pair of X chromosomes, is described. General features of chromosomes and global differences between different chromosomal regions are discussed. Abnormal karyotypes, including duplications, deficiencies, inversions, translocations and chromosome fusions are reviewed. The effects of varying ploidy and of varying gene dosage are summarized. Dosage-sensitive genes seem to be rare in C. elegans, and the organism is able to tolerate substantial levels of aneuploidy. However, autosomal hemizygosity for more than about 3 % of the total genome may be incompatible with viability.

Monica C. Vella et al. (2005) WormBook "C. elegans microRNAs."

Monica C. Vella, Frank J. Slack

[WormBook, 2005]

MicroRNAs (miRNAs) are small, non-coding regulatory RNAs found in many phyla that control such diverse events as development, metabolism, cell fate and cell death. They have also been implicated in human cancers. The C. elegans genome encodes hundreds of miRNAs, including the founding members of the miRNA family lin-4 and let-7 . Despite the abundance of C. elegans miRNAs, few miRNA targets are known and little is known about the mechanism by which they function. However, C. elegans research continues to push the boundaries of discovery in this area. lin-4 and let-7 are the best understood miRNAs. They control the timing of adult cell fate determination in hypodermal cells by binding to partially complementary sites in the mRNA of key developmental regulators to repress protein expression. For example, lin-4 is predicted to bind to seven sites in the lin-14 3'' untranslated region (UTR) to repress LIN-14 , while let-7 is predicted to bind two let-7 complementary sites in the lin-41 3'' UTR to down-regulate LIN-41 . Two other miRNAs, lsy-6 and mir-273 , control left-right asymmetry in neural development, and also target key developmental regulators for repression. Approximately one third of the C. elegans miRNAs are differentially expressed during development indicating a major role for miRNAs in C. elegans development. Given the remarkable conservation of developmental mechanism across phylogeny, many of the principles of miRNAs discovered in C. elegans are likely to be applicable to higher animals.

David Zarkower (2006) WormBook "Somatic sex determination."

David Zarkower

[WormBook, 2006]

C. elegans occurs in two natural sexes, the XX hermaphrodite and the XO male, which differ extensively in anatomy, physiology, and behavior. All somatic differences between the sexes result from the differential activity of a global sex determination regulatory pathway. This pathway also controls X chromosome dosage compensation, which is coordinated with sex determination by the action of the three SDC proteins. The SDC proteins control somatic and germline sex by transcriptional repression of the her-1 gene. HER-1 is a secreted protein that controls a regulatory module consisting of a transmembrane receptor, TRA-2 , three intracellular FEM proteins, and the zinc finger transcription factor TRA-1 . The molecular workings of this regulatory module are still being elucidated. Similarity of TRA-2 to patched receptors and of TRA-1 to GLI proteins suggests that parts of the global pathway originally derived from a Hedgehog signaling pathway. TRA-1 controls all aspects of somatic sexual differentiation, presumably by regulating a variety of tissue- and cell-specific downstream targets, including the cell death regulator EGL-1 and the male sexual regulator MAB-3 . Sex determination evolves rapidly, and conservation of sexual regulators between phyla has been elusive. An apparent exception involves DM domain proteins, including MAB-3 , which control sexual differentiation in nematodes, arthropods, and vertebrates. Important issues needing more study include the detailed molecular mechanisms of the global pathway, the identities of additional sexual regulators acting in the global pathway and downstream of TRA-1 , and the evolutionary history of the sex determination pathway. Recently developed genetic and genomic technologies and comparative studies in divergent species have begun to address these issues.

Thomas Blumenthal (2005) WormBook "Trans-splicing and operons."

Thomas Blumenthal

[WormBook, 2005]

About 70% of C. elegans mRNAs are trans-spliced to one of two 22 nucleotide spliced leaders. SL1 is used to trim off the 5'' ends of pre-mRNAs and replace them with the SL1 sequence. This processing event is very closely related to cis-splicing, or intron removal. The SL1 sequence is donated by a 100 nt small nuclear ribonucleoprotein particle (snRNP). This snRNP is structurally and functionally related to the U snRNAs (U1, U2, U4, U5 and U6) that play key roles in intron removal and trans-splicing, except that it is consumed in the process of splicing. More than half of C. elegans pre-mRNAs are subject to SL1 trans-splicing. About 30% are not trans-spliced at all. The remaining genes are trans-spliced by SL2. These genes are all downstream genes in closely spaced gene clusters similar to bacterial operons. They are transcribed from a promoter at the 5'' end of the cluster of between 2 and 8 genes. This transcription makes a polycistronic pre-mRNA that is co-transcriptionally processed by cleavage and polyadenylation at the 3'' end of each gene, and this event is closely coupled to the SL2 trans-splicing event that occurs only ~100 nt further downstream. Recent studies on the mechanism of SL2 trans-splicing have revealed that one of the 3'' end formation proteins, CstF, interacts with the only protein known to be specific to the SL2 snRNP. The operons contain primarily genes whose products are needed for mitochondrial function and the basic machinery of gene expression: transcription, splicing and translation. Many operons contain genes whose products are known to function together. This presumably provides co-regulation of these proteins by producing a single RNA that encodes both.

Robert E. Rhoads et al. (2006) WormBook "Mechanism and regulation of translation in C. elegans."

Nadejda L. Korneeva, Robert E. Rhoads, Tzvetanka D. Dinkova

[WormBook, 2006]

C. elegans represents a favorable system to study the extraordinarily complicated process of eukaryotic protein synthesis, which involves over 100 RNAs and over 200 polypeptides just for the core machinery. Initial research in protein synthesis relied on fractionated mammalian and plant systems, but in the mid-1970s, the powerful genetics of Saccharomyces cerevisiae began to yield new insights for translation in all eukaryotes. C. elegans has many features of higher eukaryotes that are not shared by yeast. This allows protein synthesis researchers to combine biochemistry, cell biology, developmental biology, genetics, and genomics to study regulation of gene expression at the translational level. Most components of the core translational machinery have been identified in C. elegans, including rRNAs, 5S RNA, tRNAs, ribosomal proteins, and aminoacyl tRNA synthetases. C. elegans has amino acid sequence homologs for 56 of the known initiation, elongation, and release factor polypeptides, but few of these have been isolated, functionally identified, or studied at the biochemical level. Similarly, C. elegans has homologs for 22 components of the major signal transduction pathways implicated in control of protein synthesis. The translational efficiency of individual mRNAs relies on cis -regulatory elements that include either a 7-methylguanosine- or 2,2,7-trimethylguanosine-containing cap, the 5''-terminal spliced leader, sequence elements in the 3''-untranslated regions, and the 3''-terminal poly(A) tract. Several key developmental pathways in C. elegans are predominantly governed by translational mechanisms. Some evidence has been presented that well described regulatory mechanisms in other organisms, including covalent modification of translation factors, sequestration of translation factors, and mRNA-specific changes in poly(A) length, also occur in C. elegans. The most interesting unexplored questions may involve changes in the translation of individual mRNAs during development, in response to physiological changes, or after genetic manipulations. Given the highly developed state of C. elegans genomics, it can be expected that future application of computational tools, including data visualization, will help detect new instances of translational control.

John Spieth (2006) WormBook "Overview of gene structure."

John Spieth

[WormBook, 2006]

Throughout the C. elegans sequencing project Genefinder was the primary protein-coding gene prediction program. These initial predictions were manually reviewed by curators as part of a "first-pass annotation" and are actively curated by WormBase staff using a variety of data and information. In the WormBase data release WS133 there are 22,227 protein-coding gene, including 2,575 alternatively-spliced forms. Twenty-eight percent of these have every base of every exon confirmed by transcription evidence while an additional 51% have some bases confirmed. Most of the genes are relatively small covering a genomic region of about 3 kb. The average gene contains 6.4 coding exons accounting for about 26% of the genome. Most exons are small and separated by small introns. The median size of exons is 123 bases, while the most common size for introns is 47 bases. Protein-coding genes are denser on the autosomes than on chromosome X, and denser in the central region of the autosomes than on the arms. There are only 561 annotated pseudogenes but estimates but several estimates put this much higher.