Iva Greenwald (2005) WormBook "LIN-12/Notch signaling in C. elegans."

Iva Greenwald

[WormBook, 2005]

Receptors of the LIN-12 /Notch family mediate cell-cell interactions during animal development, and aberrations in LIN-12 /Notch signaling have been implicated in human disease. Studies in C. elegans have been instrumental in defining the basic features of the LIN-12 /Notch pathway, the role of LIN-12 /Notch proteins as receptors for intercellular signals, the mechanism of signal transduction, and the regulation of LIN-12 /Notch signaling during cell fate decisions. This chapter is focused on detailing how the "awesome power of C. elegans genetics" has identified many core components and modulators of LIN-12 /Notch activity.

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

Frank J. Slack, Monica C. Vella

[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.

Paul W. Sternberg (2005) WormBook "Vulval development."

Paul W. Sternberg

[WormBook, 2005]

C. elegans vulval development is an intensively studied example of animal organogenesis. A network of intercellular signaling, signal transduction, and transcriptional regulation underlies the precise formation of this organ, which is the connection between the hermaphrodite uterus and the outside of the nematode. A single cell of the somatic gonad, the anchor cell, organizes the development of the vulva from epidermal precursors as well as the physical connection of the epidermis with the uterus. WNT signaling acting via the HOX gene lin-39 renders six epidermal precursor cells competent to respond to other developmental signals. The anchor cell induces nearby epidermal precursor cells to generate vulval cells via an epidermal growth factor (EGF) signaling pathway. The precise pattern of vulval precursor cell fates involves the graded action of the EGF signaling and LIN-12 (Notch) mediated lateral signaling. EGF promotes the 1 fate while LIN-12 promotes the 2 fate. Both EGF and LIN-12 prevent precursor cells from adopting the 3 fate, which generates non-specialized epidermis. EGF-receptor and Notch signaling are antagonistic: EGF-receptor signaling leads to down-regulation of the Notch-like receptor LIN-12 , while LIN-12 signaling induces negative regulators of EGF-receptor signaling such as MAP kinase phosphatase LIP-1 and the tyrosine kinase ARK-1. The 1 precursor cell generates vulE and vulF mature vulval cells; the pattern of vulE and vulF cells requires an additional signal from the anchor cell as well as WNT signaling. The two 2 precursor cells generate vulA, vulB1, vulB2, vulC and vulD cells but in mirror symmetric polar patterns: ABCD and DCBA. The reversed polarity of the posterior 2 precursor cell lineage requires WNT signaling mediated by both Frizzled class and Ryk class WNT-receptors LIN-17 and LIN-18 , respectively. A network of transcription factors controls the seven mature adult cell types; these include the LIM domain protein LIN-11 , the Pax2/5/8 protein EGL-38 , the zinc finger protein LIN-29 , and the Nkx6.1/6.2 protein COG-1. The anchor cell also patterns nearby uterine cells, via the DSL ligand LAG-2 and LIN-12 , to generate the four uv1 cells that form the tight connection with the vulva. This connection is initiated by the anchor cell, which invades between the vulF cells in a process analogous to invasive behavior of metastatic tumor cells. During this invasion process, the basement membranes between the gonad and body wall are degraded. The extensive information about vulval development in C. elegans has helped it become a paradigmatic case for identifying and studying a variety of regulatory pathways.

Lambie EJ et al. (1991) "lin-12 and glp-1: homologous genes with overlapping functions in Caenorhabditis elegans."

Kimble JE, Lambie EJ

[1991]

During the development of the nematode, Caenorhabditis elegans, cell fates are determined via a combination of cell-autonomous and cell-nonautonomous mechanisms. The latter, regulative phenomena, require the existence of one or more intercellular signaling pathways. In this review, we consider the function of two genes, lin-12 (lineage abnormal) and glp-1 (germ line proliferation defective), that are required for intercellular signaling during nematode development.

Peter G. Okkema (2005) WormBook "Transcriptional regulation."

Peter G. Okkema

[WormBook, 2005]

The regulation of transcription in C. elegans shares many similarities to transcription in other organisms. The details of how specific transcription factors bind to target promoters and act as either activators or repressors are still being examined in many cases, but an increasing number of factors and their binding sites are being characterized. This chapter reviews the general concepts that have emerged with regards to promoter function in C. elegans. Included are the methods that have been successfully employed as well as limitations encountered to date. Specific cis-acting promoter elements from myo-2 , hlh-1 and lin-26 are discussed as examples of complex promoters regulated by multiple sequence elements. In addition, examples of organ-, tissue-, and cell type-specific mechanisms for generating spatial specificity in gene expression are discussed.

Meera V. Sundaram (2006) WormBook "RTK/Ras/MAPK signaling."

Meera V. Sundaram

[WormBook, 2006]

Receptor Tyrosine Kinase (RTK)/Ras GTPase/MAP kinase (MAPK) signaling pathways are used repeatedly during metazoan development to control many different biological processes. In the nematode Caenorhabditis elegans , two different RTKs ( LET-23 /EGFR and EGL-15 /FGFR) are known to stimulate LET-60 /Ras and a MAPK cascade consisting of the kinases LIN-45 /Raf, MEK-2 /MEK and MPK-1 /ERK. This Ras/MAPK cascade is required for multiple developmental events, including induction of vulval, uterine, spicule, P12 and excretory duct cell fates, control of sex myoblast migration and axon guidance, and promotion of germline meiosis. Studies in C. elegans have provided much insight into the basic framework of this RTK/Ras/MAPK signaling pathway, its regulation, how it elicits cell-type specific responses, and how it interacts with other signaling pathways such as the Wnt and Notch pathways.

Benjamin Podbilewicz (2006) WormBook "Cell fusion."

Benjamin Podbilewicz

[WormBook, 2006]

Selective cell fusion is a natural part of development. It is found in sexually reproducing organisms that require fertilization to propagate and in muscles, placenta, bones, lens of the eye and stem cells. Cell fusion is particularly important in the development of C. elegans: in addition to 300 sperm and oocytes that fuse during fertilization, 300 of the 1090 somatic cells born, fuse throughout development. Studies of cell fusion in C. elegans have shown that although different types of cells fuse, cell membrane merger is initiated through a common mechanism involving the action of one gene, eff-1 . In worms with mutations that inactivate eff-1 , almost none of the 300 somatic cells that normally fuse do so, but appear to differentiate, attach and behave in the same way as fusing cells. Such worms develop and survive but have numerous morphological, behavioral and fertility defects associated to cell fusion failure in the epidermis, pharynx, male tail, vulva and uterus. Cell fusion in embryonic dorsal epithelial cells has been analyzed in great detail by confocal microscopy using membrane fluorescent probes, apical junction markers and cytoplasmic aqueous fluorescent probes allowing the direct observation of membrane disappearance, pore expansion and cytoplasmic content mixing. The complete elimination of the membranes between two fusing cells takes about 30 min and involves vesiculation of the fusing membranes. Genetic and cell biological evidence indicates that eff-1 activity is both necessary and sufficient to fuse epithelial and myoepithelial cells in vivo. Based on electron microscopic analyses of intermediates of cell fusion in eff-1 mutants, it appears that eff-1 is required for both initiation and expansion of fusion pores, similar to the fusogen of Influenza virus. While only one gene encoding a novel candidate component of the cell membrane fusion machinery has been found, the nematode''s cell fusion program is under the control of many cell-specific transcriptional regulators. A large number of these conserved regulators prevent cell fusion by repressing eff-1 activity. For example, if either ceh-16 /engrailed or the GATA factor EGL-18 /ELT-5 is inactivated, the lateral epidermal cells that normally do not fuse in the embryo will fuse causing embryonic lethality. And if either the Hox protein lin-39 /Deformed or its cofactor ceh-20 /Extradenticle is inactivated, the ventral epidermal vulval precursor cells that normally do not fuse in the larvae will fuse and the hermaphrodite will have no vulva. In addition, there is evidence for coordinated and complex regulation of lin-39 in the ventral epidermis by Ras, Wnt, Rb/E2F, NuRD and lin-15 pathways. It appears that in many cells that normally do not fuse, specific transcription complexes repress eff-1 expression preventing cell fusion. ref-2 (REgulator of Fusion-2) encodes a Zn-finger protein that is required to generate ventral Pn.p cells and to keep them unfused both in males and hermaphrodites. ref-2 is necessary, but not sufficient, to maintain Pn.p cells unfused. This review shows that far from cell fusion being an unusual phenomenon, there is the clear prospect that animal cells in all tissues are intrinsically programmed to fuse, and are only prevented from fusing by transcriptional and post-transcriptional control mechanisms. There are three major questions that remain open for future research: (1) How does eff-1 fuse cells? (2) How do Ras, Wnt, Rb, NuRD, E2F, heterochronic and other pathways control cell fusion? (3) What are the implications of cell fusion beyond worms?