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  Director : Mario M. Zakin (mzakin@pasteur.fr)


  abstract

 

The Unit is studying the mechanisms of transcriptional regulation of genes that are expressed specifically in certain tissues. Two models are analysed: transferrin, a plasma protein responsible for the transport of iron in the organism and a cluster of genes encoding the apolipoproteins A-I/C-III/A-IV, involved in the metabolism and transport of lipids. These studies help to understand the role and the importance of the product of each gene analysed, in both normal and pathological conditions.



  report

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Human transferrin gene expression (Bruno Baron)

Transferrin (Tf), the iron-transport protein of vertebrate serum is synthesized in hepatocytes but also in other cell-types including Sertoli cells and oligodendroctyes (OLs). We have previously found that Tf gene makes use of different combination of transcriptional factors in different subsets of cells to achieve tissue-specific expression. The laboratory is presently interested in the analysis of human Tf expression in the central nervous system (CNS), where the protein appears to have an influence on the early steps of myelinogenesis.

Transgenic mice specifically overexpressing hTf in the brain were obtained. These animals present a 30% increase of overall myelin content, distributed among its components as phospholipids, galactolipids and myelin proteins. Ultrastructural analysis by electronic microscopy shows that myelin of transgenic mice is normal in its compaction as well as in the number of wraps, and that axons appear healthier. Behavior analysis has shown that transgenic animals have also a significant increase in motor coordination abilities. Now, we have indications, obtained by in situ hybridization and immunocytochemical experiments on primary OLs cultures, that Tf expression have an impact on differentiation rate of OLs. We are actually analyzing the impact of Tf overexpression on the preliminary steps of myelination by monitoring, through IRM observations, the development of the brain of young mice. We have also shown that Tf is expressed in the retina by the glial Müller cells. We investigate the effect of overexpression of Tf, a protein which is able to fix free radicals such as metallic cations, on the troubles of the retina linked with ageing. Furthermore, we are developing the conditional invalidation of Tf in mice using the Cre-lox approach. Analysis of these animals will allow us to get a better insight of the Tf role in CNS, the retina and the Sertoli cells.

The human apolipoprotein A-I/C-III/A-IV gene cluster (Mario M. Zakin)

The apolipoprotein A-I/C-III/A-IV gene cluster is involved in the metabolism and transport of lipids. We have generated transgenic mice expressing the human cluster. These mice provide an interesting model for studies of the regulation of the three genes in combination. They are also useful for studies of the function of the proteins encoded by the three genes. Expression of the human cluster induced hyperlipidemia but reduced atherogenesis in genetically modified mice lacking apolipoprotein E. We have recently demonstrated that the expression of the human gene cluster in mice also protects against atherogenesis in response to a high fat-high cholesterol diet. Transgenic rabbits expressing the human cluster were generated in collaboration with L.M. Houdebine (INRA). Transgenic mice and rabbits are valuable models for future work on the transcriptional regulation of the human cluster, and for evaluating the effects of drugs, hormones and other agents on the expression of the three genes.

We have also generated transgenic mice expressing the human apolipoprotein A-IV. This expression reduced atherosclerotic lesions in mice lacking apolipoprotein E, without an increase in HDL cholesterol. The protection observed is accompanied by an in vivo reduction of the oxidation parameters, suggesting that human apolipoprotein A-IV acts in vivo as an antioxidant. Using our transgenic models, we are now analysing the interactions between infection, inflammation and atherosclerosis. Our first experiments show that LPS injected apoEo mice are a good model to study the influence of a chronical infection in lipid metabolism and atherosclerosis. We have recently evaluated the role of the expression of human APO A-IV in apoEo mice after administration of LPS, mimicking a systemic infection.

Keywords: Transferrin, myelinogenesis, apolipoproteins, atherosclerosis



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
  Croullebois Elisabeth –celisa@pasteur.fr Baron Bruno -bbaron@pasteur.fr

Guillou Florian –fguillou@pasteur.fr

Elfant David

Piaud Oriane – DEA student

Garcia-Otin Angel - Postdoc

Recalde Delia - Postdoc

Lamant Matthieu – DEA student


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