|HEAD||Dr. LAKOWSKI, Bernard / email@example.com|
|MEMBERS||Dr. GONTIJO, Alisson PhD Post-doc / Mme. AUBERT, Sylvie Technician / Mme GUESDON, Sylviane Secretary
The Nematode Genetics group uses the power of molecular genetics in the Nematode Caenorhabditis elegans, as well as the wealth of emerging genomic information on other nematode species, to address fundamental biological questions and biological role of homologs of certain human disease genes.
Suppressor of Presenilin (spr) genes
Presenilin genes are mutated in many cases of familial Alzheimer’s disease and are also absolutely essential for Notch signalling in animal development. We have isolated a collection of more than 100 mutations and identified several of the affected genes that by-pass the need for the C. elegans sel-12 presenilin gene. Genetic and molecular data suggests that many of the SPR proteins form a transcriptional repression complex that regulates the expression of the second presenilin gene, hop-1, and presumably other targets. Several SPR proteins are similar to components of the REST
-CoREST complex that represses the transcription of many of neuronal genes in non-neuronal tissues and in neuronal stem cells and plays a role in maintain-ing neural stem cell fate. We are characterizing the known spr genes further by genetics, Chromatin Immunoprecipitation, Immunofluorescence and DNA microarrays. We are also tying to saturate the screen and to identify additional genes that can suppress sel-12. Recently we have cloned one novel strong suppressor gene, spr-6. We have also discovered that two weak spr mutations are in core components of the Non-sense Mediated Decay (NMD) pathway, and that other NMD genes can also weakly suppress sel-12.
The DNA helicase DOG-1
DOG-1 is the C. elegans homolog of BRIP1, a human gene mutated in rare cases of Familial Breast Cancer and in Fanconi anemia. In C. elegans, the absence of dog-1 causes genomic instability at sites surrounding Guanine rich sequences that can form G-quadruplex structures. We have been doing genetic screens for spontaneous mutations in a dog-1 background to define further the spectrum of mutations induced by dog-1. In the process we have demonstrated that the unique spectrum of mutations induced by dog-1 can be very useful for creating genetic tools and for identifying new genes. Using dog-1 we have identified 15 mutations in spr-3. We have also recovered mutations in five genes that had not previously been mutated and/or identified in forward genetic screens, which we are characterising in collaboration with other C.elegans groups.
Keywords: Caenorhabditis elegans, presenilin, genetic suppression, Nonsense Mediated Decay, Alzheimer’s disease, Fanconi anemia
Bernard Lakowski, Ingele Roelens and Sandrine Jacob (2006). CoREST-like complexes regulate chromatin modification and neuronal gene expression. Journal of Molecular Neuroscience,227-239.
Submitted publications 2007
Alisson Marques Gontijo, Sylvie Aubert, Ingele Roelens, Philippe Smelty, Alberta Yen and Bernard Lakowski. Mutations in the genes involve in nonsense mediated decay ameliorate the phenotype of sel-12 presenilin mutants in Caenorhabditis elegans.
Sandrine Jacob, Delphine Bernard, Sylvie Aubert, Virgine Rubio, Olivier Poupel, and Bernard Lakowski Genetic Characterization of Mutations Arising in the Absence of DOG-1.
Activity Reports 2007 - Institut Pasteur
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