Bernard Lakowski

Determination of Life-Span in Caenorhabditis elegans by Four Clock Genes

The nematode worm Caenorhabditis elegans is a model system for the study of the genetic basis of aging. Maternal-effect mutations in four genes—clk-1, clk-2, clk-3, and gro-1— interact genetically to determine both the duration of development and life-span. Analysis of the phenotypes of these mutants suggests the existence of a general physiological clock in the worm. Mutations in certain genes involved in dauer formation (an alternative larval stage induced by adverse conditions in which development is arrested) can also extend life-span, but the life extension of Clock mutants appears to be independent of these genes. The daf-2(e1370) clk-1(e2519) worms, which carry life-span-extending mutations from two different pathways, live nearly five times as long as wild-type worms.

Molecular genetics of life span in C. elegans: how much does it teach us?

Several loci have been identified in the nematode worm Caenorhabditis elegans that, when mutated, can increase life span. Three of these genes, age-1, daf-2 and clk-1, have now been cloned. Mutations in these three genes are highly pleiotropic and affect many aspects of worm development and behaviour, age-1 and daf-2 act in the same genetic pathway and have similar effects on the worm, age-1 encodes a homologue of the p110 subunit of phosphatidylinositol 3-kinase and daf-2 encodes an insulin receptor family member, clk-1 encodes a protein of unknown biochemical function similar to the yeast metabolic regulator Cat5p/Coq7p. The implications of these findings for our understanding of organismal ageing are discussed.

Two suppressors of sel-12 encode C2H2 zinc-finger proteins that regulate presenilin transcription in Caenorhabditis elegans.

Mutations in presenilin genes are associated with familial Alzheimers disease in humans and affect LIN-12/Notch signaling in all organisms tested so far. Loss of sel-12 presenilin activity in Caenorhabditis elegans results in a completely penetrant egg-laying defect. In screens for extragenic suppressors of the sel-12 egg-laying defect, we have isolated mutations in at least five genes. We report the cloning and characterization of spr-3 and spr-4, which encode large basic C2H2 zinc-finger proteins. Suppression of sel-12 by spr-3 and spr-4 requires the activity of the second presenilin gene, hop-1. Mutations in both spr-3 and spr-4 de-repress hop-1 transcription in the early larval stages when hop-1 expression is normally nearly undetectable. As sel-12 and hop-1 are functionally redundant, this suggests that mutations in spr-3 and spr-4 bypass the need for one presenilin by stage-specifically de-repressing the transcription of the other. Both spr-3 and spr-4 code for proteins similar to the human REST/NRSF (Re1 silencing transcription factor/neural-restrictive silencing factor) transcriptional repressors. As other Spr genes encode proteins homologous to components of the CoREST co-repressor complex that interacts with REST, and the INHAT (inhibitor of acetyltransferase) co-repressor complex, our data suggest that all Spr genes may function through the same mechanism that involves transcriptional repression of the hop-1 locus.