The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

TGF-beta signal transduction.

The structure and connectivity of the nervous system of the nematode Caenorhabditis elegans has been deduced from reconstructions of electron micrographs of serial sections. The hermaphrodite nervous system has a total complement of 302 neurons, which are arranged in an essentially invariant structure. Neurons with similar morphologies and connectivities have been grouped together into classes; there are 118 such classes. Neurons have simple morphologies with few, if any, branches. Processes from neurons run in defined positions within bundles of parallel processes, synaptic connections being made en passant. Process bundles are arranged longitudinally and circumferentially and are often adjacent to ridges of hypodermis. Neurons are generally highly locally connected, making synaptic connections with many of their neighbours. Muscle cells have arms that run out to process bundles containing motoneuron axons. Here they receive their synaptic input in defined regions along the surface of the bundles, where motoneuron axons reside. Most of the morphologically identifiable synaptic connections in a typical animal are described. These consist of about 5000 chemical synapses, 2000 neuromuscular junctions and 600 gap junctions.

The structure of the nervous system of the nematode Caenorhabditis elegans

The embryonic cell lineage of the nematode Caenorhabditis elegans.

https://www.cell.com/developmental-cell/pdf/S1534-5807(04)00099-1.pdf

Development by Self-Digestion: Molecular Mechanisms and Biological Functions of Autophagy

We have found that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type. This lifespan extension, the largest yet reported in any organism, requires the activity of a second gene, daf-16. Both genes also regulate formation of the dauer larva, a developmentally arrested larval form that is induced by crowding and starvation and is very long-lived. Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation. daf-2 and daf-16 provide entry points into understanding how lifespan can be extended.

A C. elegans mutant that lives twice as long as wild type

The nematode Caenorhabditis elegans responds to overcrowding and scarcity of food by arresting development as a dauer larva, a nonfeeding, long-lived, stress-resistant, alternative third-larval stage. Previous work has shown that mutations in the genes daf-2 (encoding a member of the insulin receptor family) and age-1 (encoding a PI 3-kinase) result in constitutive formation of dauer larvae (Daf-c), increased adult longevity (Age), and increased intrinsic thermotolerance (Itt). Some daf-2 mutants have additional developmental, behavioral, and reproductive defects. We have characterized in detail 15 temperature-sensitive and 1 nonconditional daf-2 allele to investigate the extent of daf-2 mutant defects and to examine whether specific mutant traits correlate with each other. The greatest longevity seen in daf-2 mutant adults was approximately three times that of wild type. The temperature-sensitive daf-2 mutants fell into two overlapping classes, including eight class 1 mutants, which are Daf-c, Age, and Itt, and exhibit low levels of L1 arrest at 25.5 degrees. Seven class 2 mutants also exhibit the class 1 defects as well as some or all of the following: reduced adult motility, abnormal adult body and gonad morphology, high levels of embryonic and L1 arrest, production of progeny late in life, and reduced brood size. The strengths of the Daf-c, Age, and Itt phenotypes largely correlated with each other but not with the strength of class 2-specific defects. This suggests that the DAF-2 receptor is bifunctional. Examination of the null phenotype revealed a maternally rescued egg, L1 lethal component, and a nonconditional Daf-c component. With respect to the Daf-c phenotype, the dauer-defective (Daf-d) mutation daf-12(m20) was epistatic to daf-2 class 1 alleles but not the severe class 2 alleles tested. All daf-2 mutant defects were suppressed by the daf-d mutation daf-16(m26). Our findings suggest a new model for daf-2, age-1, daf-12, and daf-16 interactions.

/pdf/two-pleiotropic-classes-of-daf-2-mutation-affect-larval-16ck5cibxv.pdf

Two Pleiotropic Classes of daf-2 Mutation Affect Larval Arrest, Adult Behavior, Reproduction and Longevity in Caenorhabditis elegans

The nematode Caenorhabditis elegans responds to conditions of overcrowding and limited food by arresting development as a dauer larva. Genetic analysis of mutations that alter dauer larva formation (daf mutations) is presented along with an updated genetic pathway for dauer vs. nondauer development. Mutations in the daf-2 and daf-23 genes double adult life span, whereas mutations in four other dauer-constitutive genes positioned in a separate branch of this pathway (daf-1, daf-4, daf-7 and daf-8) do not. The increased life spans are suppressed completely by a daf-16 mutation and partially in a daf-2; daf-18 double mutant. A genetic pathway for determination of adult life span is presented based on the same strains and growth conditions used to characterize Daf phenotypes. Both dauer larva formation and adult life span are affected in daf-2; daf-12 double mutants in an allele-specific manner. Mutations in daf-12 do not extend adult life span, but certain combinations of daf-2 and daf-12 mutant alleles nearly quadruple it. This synergistic effect, which does not equivalently extend the fertile period, is the largest genetic extension of life span yet observed in a metazoan.

https://www.genetics.org/content/genetics/139/4/1567.full.pdf

Genes that regulate both development and longevity in Caenorhabditis elegans.

The Caenorhabditis elegans dauer larva is specialized for dispersal without growth and is formed under conditions of overcrowding and limited food. The daf-7 gene, required for transducing environmental cues that support continuous development with plentiful food, encodes a transforming growth factor-β (TGF-β) superfamily member. A daf-7 reporter construct is expressed in the ASI chemosensory neurons. Dauer-inducing pheromone inhibits daf-7 expression and promotes dauer formation, whereas food reactivates daf-7 expression and promotes recovery from the dauer state. When the food/pheromone ratio is high, the level of daf-7 mRNA peaks during the L1 larval stage, when commitment to non-dauer development is made.

https://science.sciencemag.org/content/sci/274/5291/1389.full.pdf

Control of C. elegans Larval Development by Neuronal Expression of a TGF-β Homolog

The dauer larva of Caenorhabditis elegans is a developmentally arrested stage induced by starvation or overcrowding. Mutant genes controlling the ability to form dauer larvae interact in a way which allows them to be ordered in a pathway. Mutant phenotypes suggest that the pathway corresponds to neural processing of environmental stimuli.

Interacting genes in nematode dauer larva formation

I. INTRODUCTION Dauer larvae were first identified as a special larval stage of insect-parasitic nematodes. These larvae, which differed structurally from all other stages of the same species, were termed “dauerlarven” by Fuchs (1915). The dauer (enduring) stage of Caenorhabditis elegans is formed when environmental conditions are inadequate for successful reproduction. In abundant food, the animal develops continuously through the four larval stages (L1–L4) to the adult. Coincident with increased population density and limited food supply, development is arrested at the second molt, and the third-stage larva that is formed is structurally and behaviorally specialized for dispersal and long-term survival (Cassada and Russell 1975). Dauer larvae do not feed, but they can survive at least four to eight times the normal 2-week life span of C. elegans (Klass and Hirsh 1976). When favorable conditions are encountered, the dauer larva begins to feed and resumes development to the adult. Both entry into and exit from the dauer stage are developmental responses to specific chemosensory cues. These cues inform the larva whether there will be sufficient food available to support its reproduction. The environmental cues are first assessed and integrated throughout the L1 stage (Golden and Riddle 1984b). The primary cue is a Caenorhabditis-specific pheromone constitutively released by the nematodes (Golden and Riddle 1984c). The pheromone is very stable and hydrophobic and has chromatographic properties similar to those of hydroxylated fatty acids and bile acids. The concentration of pheromone reflects nematode population density. Temperature and food modulate the response to pheromone...

Patrice S. Albert

Papers

Two Pleiotropic Classes of daf-2 Mutation Affect Larval Arrest, Adult Behavior, Reproduction and Longevity in Caenorhabditis elegans

Genes that regulate both development and longevity in Caenorhabditis elegans.

Control of C. elegans Larval Development by Neuronal Expression of a TGF-β Homolog

Interacting genes in nematode dauer larva formation

Genetic and Environmental Regulation of Dauer Larva Development