Que peut nous apprendre un ver sur le fonctionnement du cerveau humain? Les donnees acquises sur le systeme nerveux du nematode Caenorhabditis elegans demontrent l’existence d’une fascinante conservation de la biologie moleculaire et cellulaire du neurone au travers de plus de 550 millions d’annees d’evolution separant les nematodes des mammiferes. C. elegans possede un systeme nerveux simple forme de 302 neurones et d’environ 7000 synapses. Des outils genetiques puissants permettent d’isoler de nouveaux genes et d’attribuer a des genes connus de nouvelles fonctions dans la mise en place et le fonctionnement du reseau neuronal du nematode. Nous montrerons par quelques exemples comment les decouvertes faites chez C. elegans ont pu etre rapidement transposees a la biologie du systeme nerveux des mammiferes.

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C. elegans : des neurones et des gènes

The synaptic vesicle cycle at the nerve terminal consists of vesicle exocytosis with neurotransmitter release, endocytosis of empty vesicles, and regeneration of fresh vesicles. Of all cellular transport pathways, the synaptic vesicle cycle is the fastest and the most tightly regulated. A convergence of results now allows formulation of molecular models for key steps of the cycle. These developments may form the basis for a mechanistic understanding of higher neural function.

The synaptic vesicle cycle: a cascade of protein–protein interactions

Experimental Neurology By Prof Paul Glees Pp xii + 532 (Oxford: Clarendon Press; London: Oxford University Press, 1961) 75s net

The Nervous System

▪ Abstract Membrane fusion involves the merger of two phospholipid bilayers in an aqueous environment. In artificial lipid bilayers, fusion proceeds by means of defined transition states, including hourglass-shaped intermediates in which the proximal leaflets of the fusing membranes are merged whereas the distal leaflets are separate (fusion stalk), followed by the reversible opening of small aqueous fusion pores. Fusion of biological membranes requires the action of specific fusion proteins. Best understood are the viral fusion proteins that are responsible for merging the viral with the host cell membrane during infection. These proteins undergo spontaneous and dramatic conformational changes upon activation. In the case of the paradigmatic fusion proteins of the influenza virus and of the human immunodeficiency virus, an amphiphilic fusion peptide is inserted into the target membrane. The protein then reorients itself, thus forcing the fusing membranes together and inducing lipid mixing. Fusion of intr...

Membrane Fusion and Exocytosis

Low caloric intake (caloric restriction) can lengthen the life span of a wide range of animals and possibly even of humans. To understand better how caloric restriction lengthens life span, we used genetic methods and criteria to investigate its mechanism of action in the nematode Caenorhabditis elegans. Mutations in many genes (eat genes) result in partial starvation of the worm by disrupting the function of the pharynx, the feeding organ. We found that most eat mutations significantly lengthen life span (by up to 50%). In C. elegans, mutations in a number of other genes that can extend life span have been found. Two genetically distinct mechanisms of life span extension are known: a mechanism involving genes that regulate dauer formation (age-1, daf-2, daf-16, and daf-28) and a mechanism involving genes that affect the rate of development and behavior (clk-1, clk-2, clk-3, and gro-1). We find that the long life of eat-2 mutants does not require the activity of DAF-16 and that eat-2; daf-2 double mutants live even longer than extremely long-lived daf-2 mutants. These findings demonstrate that food restriction lengthens life span by a mechanism distinct from that of dauer-formation mutants. In contrast, we find that food restriction does not further increase the life span of long-lived clk-1 mutants, suggesting that clk-1 and caloric restriction affect similar processes.

https://www.pnas.org/content/pnas/95/22/13091.full.pdf

The genetics of caloric restriction in Caenorhabditis elegans

Genes affecting acetylcholine (ACh) levels without influencing choline acetyltransferase activity have been identified in Caenorhabditis elegans. We have examined one such gene, unc-18. We isolated a transposon-insertion allele for unc-18 and used it to clone a genomic region containing the unc-18 locus. The unc-18 location within this region was determined by rescuing the unc-18 mutant phenotype in a germline transformation experiment and identifying transcripts affected by four independent unc-18 mutations. A single-sized poly(A)+ RNA was synthesized from the gene. Expression of the transcript appears to be stage specific: The transcript is found in abundance at the early larval stage but in decreased amounts at the fourth larval and the adult stages. These results show that the unc-18 gene plays a role in development as well as in the kinetics of ACh metabolism.

The unc-18 gene encodes a novel protein affecting the kinetics of acetylcholine metabolism in the nematode Caenorhabditis elegans.

The Caenorhabditis elegans unc-13,unc-18, and unc-64 genes are required for normal synaptic transmission. The UNC-18 protein binds to theunc-64 gene product C. elegans syntaxin (Ce syntaxin). However, it is not clear how this protein complex is regulated. We show that UNC-13 transiently interacts with the UNC-18-Ce syntaxin complex, resulting in rapid displacement of UNC-18 from the complex. Genetic and biochemical evidence is presented that UNC-13 contributes to the modulation of the interaction between UNC-18 and Ce syntaxin.

https://www.jneurosci.org/content/jneuro/19/12/4772.full.pdf

Ryuji Hosono

Papers

The unc-18 gene encodes a novel protein affecting the kinetics of acetylcholine metabolism in the nematode Caenorhabditis elegans.

Regulation of the UNC-18-Caenorhabditis elegans syntaxin complex by UNC-13.

The C. elegans unc-18 gene encodes a protein expressed in motor neurons.

Age-dependent changes in mobility and separation of the nematode Caenorhabditis elegans.

Alterations of life span in the nematode Caenorhabditis elegans under monoxenic culture conditions