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  Gdiff


  Director : Mary C. Weiss (mweiss@pasteur.fr)


  abstract

 

Studies of hepatic differentiation and of bipotential liver stem cells have led to the conclusion that HNF4 is key for this differentiation, and regulation of its gene is being analyzed. The PKA regulatory subunit R1a gene contains five promoters that result in five different transcripts that differ only in the 5'UTR sequences; functional analysis of these promoters is underway.
In addition, the mechanisms of localisation of the protein are analysed.



  report

cale

The Unit of Genetics of Differentiation uses cell genetics to analyse the roles of different Liver Enriched Transcription Factors (LETF) in the establishment and maintenance of the differentiated hepatic phenotype. It has been shown that in dedifferentiated rat hepatoma cells, the forced expression of HNF4 cDNA is sufficient to provoke the re-expression of genes that are considered markers of hepatic differentiation. In addition, in some cell lines of hepatic origin which fail to express either the LETF or hepatocyte differentiation, the forced expression of either HNF1a or of HNF4 cDNA is sufficient to ensure the expression of the endogenous genes for both factors, indicating the existence of a reciprocal regulatory loop between these two key transcription factors. In current experiments an enhancer of expression of the HNF4 gene is being analyzed in order to identify the factors implicated in the activation of HNF4 expression. Liver cells from transgenic mice expressing a constituitively active HGF/SF receptor Met are premissive for immortalization and are non-transformed. These lines harbor a bi-potential precurser cell, designated palmate, that is competent to differentiate into hepatocytes or bile duct cells. These percursor cells, of speading morphology that we have baptised palmate, express neither LETF nor hepatic functions. FGF induces transition of the palmate cells to an epithelial form, while TGFb stabilizes the palmate phenotype. Experiments underway investigate further the differentiation potential of palmate cells and their epithelial derivatives. Analysis of expression of the RIa regulatory subunit of the cAMP dependent protein kinase and its role in heptocyte differentiation has led to the discovery of a series of alternate promoters of the gene. Use of the alternative promoters provides different 5'-UTR sequences without any change in the corresponding protein. Analysis of the promoter usage in different tissues has revealed that they are expressed in both a ubiquitous and tissue restricted fashion. In particular, the 5'exon designated 1c is found predominately in the testis while 1a transcripts accumulate at the neuromuscular junction. The amino acids that are critical for this localisation have been identified. RIa is also localised to microtubule in interphase and during mitosis. Over-expresssion of RIa leads to a high frequency of abberrant mitosis implying a critical role for RIain mitotic progression.



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
 

Papelard Solange, IP, papelard@pasteur.fr

Bailly Alain, INSERM, abailly@pasteur.fr

Faust Daniela, IP, dfaust@pasteur.fr

Hayhurst Graham, CNRS

Imaizumi-Scherrer Tereza, CNRS, mayumi@pasteur.fr

Weiss Mary, CNRS/IP, mweiss@pasteur.fr

Briançon Nadège, Etudiante en thèse, nbrianco@pasteur.fr

Bristeau Anne, Etudiante en thèse, bristeau@pasteur.fr

Strick Hélène, Etudiante en thèse, hstrick@pasteur.fr

Torres-Padilla Maria-Elena, Etudiante en thèse, mtorres@pasteur.fr

Catherin Anne-Marie, IP, acatheri@pasteur.fr

Deschatrette Catherine, CNRS, cdeschat@pasteur.fr

Mulet Céline, IP, cmulet@pasteur.fr


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