[
Adv Exp Med Biol,
2013]
The germline of Caenorhabditis elegans derives from a single founder cell, the germline blastomere P(4). P(4) is the product of four asymmetric cleavages that divide the zygote into distinct somatic and germline (P) lineages. P(4) inherits a specialized cytoplasm ("germ plasm") containing maternally encoded proteins and RNAs. The germ plasm has been hypothesized to specify germ cell fate, but the mechanisms involved remain unclear. Three processes stand out: (1) inhibition of mRNA transcription to prevent activation of somatic development, (2) translational regulation of the nanos homolog
nos-2 and of other germ plasm mRNAs, and (3) establishment of a unique, partially repressive chromatin. Together, these processes ensure that the daughters of P(4), the primordial germ cells Z2 and Z3, gastrulate inside the embryo, associate with the somatic gonad, initiate the germline transcriptional program, and proliferate during larval development to generate 2,000 germ cells by adulthood.
[
Philos Trans R Soc Lond B Biol Sci,
2013]
To become polarized, cells must first 'break symmetry'. Symmetry breaking is the process by which an unpolarized, symmetric cell develops a singularity, often at the cell periphery, that is used to develop a polarity axis. The Caenorhabditis elegans zygote breaks symmetry under the influence of the sperm-donated centrosome, which causes the PAR polarity regulators to sort into distinct anterior and posterior cortical domains. Modelling analyses have shown that cortical flows induced by the centrosome combined with antagonism between anterior and posterior PARs (mutual exclusion) are sufficient, in principle, to break symmetry, provided that anterior and posterior PAR activities are precisely balanced. Experimental evidence indicates, however, that the system is surprisingly robust to changes in cortical flows, mutual exclusion and PAR balance. We suggest that this robustness derives from redundant symmetry-breaking inputs that engage two positive feedback loops mediated by the anterior and posterior PAR proteins. In particular, the PAR-2 feedback loop stabilizes the polarized state by creating a domain where posterior PARs are immune to exclusion by anterior PARs. The two feedback loops in the PAR network share characteristics with the two feedback loops in the Cdc42 polarization network of Saccharomyces cerevisiae.
[
Genes Dev,
1999]
A wide variety of extracellular stimuli induce signal transduction through receptors coupled to heterotrimeric G proteins, which consist of alpha, beta, and gamma subunits (Gilman 1987). The G alpha subunit has guanine nucleotide binding and GTP hydrolysis activities. Based on function and amino acid sequence homology, the Galpha, G alph i/o, G alpha q, and G alpha 12 (Simon et al. 1991; Hepler and Gilman 1992). As exemplified by the responsiveness of our five senses to environmental stimuli, signaling mediated by trimeric G proteins is often extremely rapid and transient. A key step in achieving such a raid response is the ability of the G alpha subunit to switch between it GDP- and GTP-bound forms. The nucleotide binding state of G alpha is regulated at both the GDP dissociation and GTP hydrolysis steps. Stimulation of receptors by agonists leads to a conformational change in the receptors which can function as a guanine nucleotide exchange factor to stimulate a rapid dissociation of GDP from the inactive G alpha. The nucleotide-free G alpha is then available to bind GTP, leading to the dissociation of G alpha from the G beta gamma heterodimer. Both the G alpha and G beat gamma subunits can interact with and regulate downstream effectors that include adenylyl cyclase, phospholipase C, and ion channels (Gilman 1987; Birnbaumer 1992).
[
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.
[
Prog Mol Biol Transl Sci,
2009]
The nematode worm, Caenorhabditis elegans, contains orthologs of most regulator of G protein signaling (RGS) protein subfamilies and all four G protein -subunit subfamilies found in mammals. Every C. elegans RGS and G gene has been knocked out, and the in vivo functions and G targets of a number of RGS proteins have been characterized in detail. This has revealed a complex relationship between the RGS and G proteins, in which multiple RGS proteins can regulate the same G protein, either by acting redundantly or by exerting control over signaling under different circumstances or in different cells. RGS proteins that are coexpressed can also show specificity for distinct G targets in vivo, and the determinants of such specificity can reside outside of the RGS domain. This review will discuss how analysis in C. elegans may aid us in achieving a full understanding of the physiological functions of RGS proteins.