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  Director : LAKOWSKI, Bernard (lakowski@pasteur.fr)


  abstract

 

We are using the Nematode Caenorhabditis elegans to study genetic modifiers of the presenilin genes. Presenilins are essential for animal development and mutations in the human homologues cause Familial Alzheimer's disease. We have identified several suppressors of one C. elegans presenilin gene (spr genes) that normally repress the expression of a second presenilin. The human homologues of these genes are involved in transcriptional repression and limit the expression of many neuronal genes to neuronal cell types.



  report

cale

The Nematode Caenorhabditis elegans is a powerful model system to study neurobiology and development. We are using C. elegans to study the genetics of presenilin genes. Presenilins are polytopic proteins that are found as part of a high molecular weight complex that cleaves certain types of type I transmembrane proteins in the middle of the transmembrane domain. Mutations in the mammalian presenilin genes lead to Familial Alzheimer's Disease by affecting the processing of the Amyloid Precursor Protein (APP). In all animals, presenilin genes are essential for normal development as they are necessary for the activation of Notch-type receptors.

To try to understand more about this important class of proteins, we have been using genetic approaches in C. elegans to identify factors that can modify the effect of mutations in presenilin genes. Loss of sel-12 presenilin activity in C. elegans results in a strong egg-laying defect. In screens for suppressors of this defect, we identified 25 mutations that define at least six suppressors of presenilin (spr) genes. Five of these genes have been cloned and characterized to date. The identities and genetics of these genes suggest that they may all be part of a single complex. We have cloned and characterized the genes spr-3 and spr-4. spr-3 and spr-4 encode C2H2 zinc finger proteins that weakly resemble one another, as well as the human REST (RE1 Silencing Transcription Factor, also known as NRSF) transcriptional repressor. REST is required for the transcriptional repression of many neuron specific genes, such as ion channels, in non-neuronal cell types. REST does this by recruiting two separate co-repressor complexes, Sin3 and CoREST, which both have histone deacetylase activity. Two other spr genes, spr-1 and spr-5, encode C. elegans homologues of core components of the CoREST co-repressor complex. SPR-5 is a polyamine oxidase-like protein, while SPR-1 is homologous to CoREST itself (Sophie Jarriault and Iva Greenwald Genes & Dev. 2002). We cloned and characterized spr-5 and have also shown that SPR-1 and SPR-5 interact physically. The suppression of sel-12 by all spr mutations requires the activity of a second presenilin, hop-1. Mutations in spr-3, spr-4 and spr-5 increase the level of the hop-1 transcript in the early larval stages, when it is normally extremely low. Altogether, this suggests that SPR-3 and SPR-4 may act as transcriptional repressors that normally repress the transcription of hop-1 by recruiting a co-repressor complex similar to CoREST to the hop-1 locus. Mutations in any of these components remove this repression and allow hop-1 to be expressed strongly enough to compensate for the defect in sel-12.

The CoREST complex has recently been shown to link local modification of core histones to regional chromatin silencing. Silencing of different genomic regions is essential for the maintenance of a cell's fate, whether it is a fully differentiated neuron or a stem cell, and defects in silencing are associated with cancer. The C. elegans spr genes provide a genetic model to address the biological and biochemical function of CoREST-like complexes and their associated transcription factors.

Keywords: suppressors, transcriptional repression, silencing, Caenorhabditis elegans, Alzheimer’s disease



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
    LAKOWSKI, Bernard, Pasteur Institute, group leader (lakowski@pasteur.fr)   POUPEL, Olivier, senior technician, (opoupel@pasteur.fr)

Activity Reports 2002 - Institut Pasteur
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