[
WormBook,
2006]
Heterotrimeric G proteins, composed of alpha , beta , and gamma subunits, are able to transduce signals from membrane receptors to a wide variety of intracellular effectors. In this role, G proteins effectively function as dimers since the signal is communicated either by the G alpha subunit or the stable G betagamma complex. When inactive, G alpha -GDP associates with G betagamma and the cytoplasmic portion of the receptor. Ligand activation of the receptor stimulates an exchange of GTP for GDP resulting in the active signaling molecules G alpha -GTP and free G betagamma , either of which can interact with effectors. Hydrolysis of GTP restores G alpha -GDP, which then reassociates with G betagamma and receptor to terminate signaling. The rate of G protein activation can be enhanced by the guanine-nucleotide exchange factor, RIC-8 , while the rate of GTP hydrolysis can be enhanced by RGS proteins such as EGL-10 and EAT-16 . Evidence for a receptor-independent G-protein-signaling pathway has been demonstrated in C. elegans early embryogenesis. In this pathway, the G alpha subunits GOA-1 and GPA-16 are apparently activated by the non-transmembrane proteins GPR-1 , GPR-2 , and RIC-8 , and negatively regulated by RGS-7 . The C. elegans genome encodes 21 G alpha , 2 G beta and 2 G gamma subunits. The alpha subunits include one ortholog of each mammalian G alpha family: GSA-1 (Gs), GOA-1 (Gi/o), EGL-30 (Gq) and GPA-12 (G12). The remaining C. elegans alpha subunits ( GPA-1 , GPA-2 , GPA-3 , GPA-4 , GPA-5 , GPA-6 , GPA-7 , GPA-8 , GPA-9 , GPA-10 , GPA-11 , GPA-13 , GPA-14 , GPA-15 , GPA-16 , GPA-17 and ODR-3 ) are most similar to the Gi/o family, but do not share sufficient homology to allow classification. The conserved G alpha subunits, with the exception of GPA-12 , are expressed broadly while 14 of the new G alpha genes are expressed in subsets of chemosensory neurons. Consistent with their expression patterns, the conserved C. elegans alpha subunits, GSA-1 , GOA-1 and EGL-30 are involved in diverse and fundamental aspects of development and behavior. GOA-1 acts redundantly with GPA-16 in positioning of the mitotic spindle in early embryos. EGL-30 and GSA-1 are required for viability starting from the first larval stage. In addition to their roles in development and behaviors such as egg laying and locomotion, the EGL-30 , GSA-1 and GOA-1 pathways interact in a network to regulate acetylcholine release by the ventral cord motor neurons. EGL-30 provides the core signals for vesicle release, GOA-1 negatively regulates the EGL-30 pathway, and GSA-1 modulates this pathway, perhaps by providing positional cues. Constitutively activated GPA-12 affects pharyngeal pumping. The G alpha subunits unique to C. elegans are primarily involved in chemosensation. The G beta subunit, GPB-1 , as well as the G gamma subunit, GPC-2 , appear to function along with the alpha subunits in the classic G protein heterotrimer. The remaining G beta subunit, GPB-2 , is thought to regulate the function of certain RGS proteins, while the remaining G gamma subunit, GPC-1 , has a restricted role in chemosensation. The functional difference for most G protein pathways in C. elegans, therefore, resides in the alpha subunit. Many cells in C. elegans express multiple G alpha subunits, and multiple G protein pathways are known to function in specific cell types. For example, Go, Gq and Gs-mediated signaling occurs in the ventral cord motor neurons. Similarly, certain amphid neurons use multiple G protein pathways to both positively and negatively regulate chemosensation. C. elegans thus provides a powerful model for the study of interactions between and regulation of G protein signaling.
[
Human Genome News,
1999]
For the first time, scientists have the nearly complete genetic instructions for an animal that, like humans, has a nervous system, digests food, and reproduces sexually. The 97-million-base genome of the tiny roundworm Caenorhabditis elegans was deciphered by an international team led by Robert Waterston and John Sulston. The work was reported in a special issue of the journal Science (December 11, 1998) that featured six articles describing the history and significance of the accomplishment and some early sequence-analysis results.
[
Biochim Biophys Acta,
2002]
UDP-N-acetylglucosamine:alpha-3-D-mannoside
beta-1,2-N-acetylglucosaminyltransferase I (GnT I) and UDP-N-acetylglucosamine:alpha-6-D-mannoside
beta-1,2-N-acetylglucosaminyltransferase II (GnT 11) are key enzymes in the synthesis of Asn-linked hybrid and complex glycans. We have cloned cDNAs from Caenorhabditis elegans for three genes homologous to mammalian GnT I (designated
gly-12,
gly-13 and
gly-14) and one gene homologous to mammalian GnT II. All four cDNAs encode proteins which have the domain structure typical of previously cloned Golgi-type glycosyltransferases and show enzymatic activity (GnT I and GnT 11, respectively) on expression in transgenic worms. We have isolated worm mutants lacking the three GnT I genes by the method of ultraviolet irradiation in the presence of trimethylpsoralen (TMP); null mutants for GnT 11 have not yet been obtained. The
gly-12 and
gly-14 mutants as well as the
gly-14;
gly-12 double mutant displayed wild-type phenotypes indicating that neither
gly-12 nor
gly-14 is necessary for worm development under standard laboratory conditions. This finding and other data indicate that the GLY-13 protein is the major functional GnT I in C elegans. The mutation lacking the
gly-13 gene is partially lethal and the few survivors display severe morphological and behavioral defects. We have shown that the observed phenotype co-segregates with the
gly-13 deletion in genetic mapping experiments although a second mutation near the
gly-13 gene cannot as yet be ruled out. Our data indicate that complex and hybrid N-glycans may play critical roles in the morphogenesis of C elegans, as they have been shown
[
Bioessays,
1994]
During development, one mechanism for generating different cell types is asymmetric cell division, by which a cell divides and contributes different factors to each of its daughter cells. Asymmetric cell division occurs throughout the eukaryotic kingdom, from yeast to humans. Many asymmetric cell divisions occur in a defined orientation. This implies a cellular mechanism for sensing direction, which must ultimately lead to differences in gene expression between two daughter cells. In this review, we describe two classes of molecules: regulatory factors that are differentially expressed upon asymmetric cell division, and components of a signal transduction pathway that may define cell polarity. The
lin-11 and
mec-3 genes of C. elegans, the Isl-1 gene of mammals and the HO gene of yeast, encode regulatory factors that determine cell type of one daughter after asymmetric cell division. The CDC24 and CDC42 genes of yeast affect both bud positioning and orientation of mating projections, and thus may define a general cellular polarity. We speculate that molecules such as Cdc24 and Cdc42 may regulate expression of genes such as
lin-11,
mec-3, Isl-1 and HO upon asymmetric cell division.
[
Sci STKE,
2003]
Examples of the activation of heterotrimeric G proteins in vivo by any means other than through activated cell surface receptors have been limited to pathophysiological phenomena. With the discovery of proteins apart from receptors that facilitate guanine nucleotide exchange and affect G protein subunit dissociation directly, however, the notion of receptor-independent modes of activation in normal circumstances has become a subject of great interest. Three recent publications, each focusing on G protein regulators (GPRs) in asymmetric positioning of the mitotic spindle in the early Caenorhabditis elegans embryo, provide substantial support for the likelihood of such a form of activation. The C. elegans proteins GPR-1 and GPR-2 each contain a G protein regulatory motif, which supports interaction with Galpha(i)-like subunits. Inactivation of the genes encoding GPR-1 and GPR-2 prevents the correct positioning of the mitotic spindle in the one- and two-cell embryo. This phenotype is identical to that achieved by inactivation of genes encoding the Galpha subunits GOA-1 and GPA-16. Because signaling in the one- and two-cell embryos is "intrinsic," the data suggest a GPR-dependent, receptor-independent mode of G protein activation. The GPRs interact preferentially with the guanosine diphosphate (GDP)-bound form of alpha subunits, and the GPR motif per se exhibits GDP dissociation inhibitor activity. The actions of the GPRs imply that GDP.Galpha.GPR is a key intermediate or effector in force generation relevant to
[
Traffic,
2002]
In eukaryotic cells members of the kinesin family mediate intracellular transport by carrying cellular cargo on microtubule tracks. The nematode Caenorhabditis elegans genome encodes 21 members of the kinesin family, which show significant homology to their mammalian orthologs. Based on motor domain sequence homology and placement of the motor domain in the protein, the C. elegans kinesins have been placed in eight distinct groups; members of which participate in embryonic development, protein transport, synaptic membrane vesicles movement and in the axonal growth. Among 21 kinesins, at least 11 play a central role in spindle movement and chromosomal segregation. Understanding the function of C. elegans kinesins and related proteins may help navigate through the intricacies of intracellular traffic in a simple animal.
[
WormBook,
2014]
Polarity establishment, asymmetric division, and acquisition of cell fates are critical steps during early development. In this review, we discuss processes that set up the embryonic axes, with an emphasis on polarity establishment and asymmetric division. We begin with the first asymmetric division in the C. elegans embryo, where symmetry is broken by the local inactivation of actomyosin cortical contractility. This contributes to establishing a polarized distribution of PAR proteins and associated components on the cell cortex along the longitudinal embryonic axis, which becomes the anterior-posterior (AP) axis. Thereafter, AP polarity is maintained through reciprocal negative interactions between the anterior and posterior cortical domains. We then review the mechanisms that ensure proper positioning of the centrosomes and the mitotic spindle in the one-cell embryo by exerting pulling forces on astral microtubules. We explain how a ternary complex comprised of G (GOA-1/GPA-16), GPR-1/GPR-2, and LIN-5 is essential for anchoring the motor protein dynein to the cell cortex, where it is thought to exert pulling forces on depolymerizing astral microtubules. We proceed by providing an overview of cell cycle asynchrony in two-cell embryos, as well as the cell signaling and spindle positioning events that underly the subsequent asymmetric divisions, which establish the dorsal-ventral and left-right axes. We then discuss how AP polarity ensures the unequal segregation of cell fate regulators via the cytoplasmic proteins MEX-5/MEX-6 and other polarity mediators, before ending with an overview of how the fates of the early blastomeres are specified by these processes.