Stéphane Schurmans

Identification and characterization of mRNAs differentially expressed in thyroid cells stimulated by a mitogenic treatment

The aim of our work is to identify new genes and proteins involved in the control of the proliferation of thyroid cells as putative protooncogenes and antioncogenes. Several strategies are discussed. A first study has allowed to identify three new genes. Further search will use the differential display and gene arrays methodology. The role of the identified proteins coded by the genes is studied in vitro by the search of partner proteins by the double hybrid method and in vivo by mice gene knockout technology.

P1-033: Expression of inositol 1,4,5-trisphosphate 3-kinase B in Alzheimer's disease and in transgenic models

EGF-like ligand Neuregulin-1 (NRG1), and its receptors, members of the ErbB receptor tyrosine kinase family are also substrates for regulated intramembraneous proteolysis mediated by -secretase. Recently the cleavage of NRG1 was shown to be deficient in BACE1 -/mice. The reduced cleavage of NRG1 prevents its biological activity and results in peripheral hypomyelination. Methods: We investigated whether BACE1 can influence the release of the active EGF domain and thereby potentially regulates paracrine or juxtacrine NRG1 signaling. Compound mutant mice were generated by crossing NRG1 mutants in the BACE1 -/mouse background. BACE1 inhibitors were applied on cell cultures for biochemical experiments and in vivo in mice. Results: Very high levels of BACE1 were observed at time points when peripheral nerves become myelinated. Biochemical analysis revealed a preferential cleavage of certain NRG isoforms by BACE1 which results in the release of the EGF domain. BACE1 is required for myelination and correct bundling of axons by Schwann cells most likely via processing of type III NRG1. Compound mutants show a higher degree of hypomyelination indicating for compensatory mechanisms of BACE1 dependent NRG1 cleavage. TACE eventually compensates for BACE1. Reduction of soluble A 1-40 levels in brain homogenates was observed in concert with an accumulation of unprocessed full length NRG1 within 2 hours after inhibitor treatment. Conclusions: These studies confirm genetically and pharmacologically, that BACE-1 plays the predominant role in the -site cleavage of NRG and that inhibition of -secretase activity could potentially interfere with NRG signaling.