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UMR 7286 - Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille

T. Brue team

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Roles of Transcription Factors and Clock Genes-In Pituitary Pathophysiology

Our group focuses on pituitary transcription factors and studies their roles and mechanisms of action in the physiology and pathophysiology of the pituitary. Three main directions are followed.

T. Brue team

1- Physiopathology.

In relation with a large multicentric clinical network aimed at the study of human hypopituitarisms of genetic origin and coordinated by T. Brue ("Genhypopit"), we screen transcription factor genes known for their involvement in pituitary development (Hesx1, Lhx3 and 4, Pitx1 and 2, Prop1, Pou1F1/Pit1, Tpit, etc) for new mutations that might be responsible for pituitary deficits (Reynaud et al., JCEM, 2006, 91:3329). The functional consequences of identified mutations are evaluated using in vitro approaches (DNA binding, transactivation of known target promoters, subcellular localization). For pituitary deficits of unknown etiology, we are trying to identify new genes the mutation of which could be responsible for these deficits, using a "candidate gene" approach and/or genetic approaches.

2- Role of Pit-1/POU1F1 in the regulation of cell proliferation and death. Search for new targets and partners.

Using dominant negative mutants of Pou1F1/Pit-1, we have shown that this transcription factor exerts an anti-apoptotic and pro-proliferative role that can be observed in somatolactotrop cells but not in heterologous cells including non-somatolactotrop cells of pituitary origin (Pellegrini et al., Mol. Endocrinol., 2006, 20:3212). This observation suggests the existence of new transcriptional targets that we are trying to identify through the use of DNA arrays and chromatin immunoprecipitation (ChIP-Chip). In parallel, new partners of this transcription factor are also sought for, using co-immunoprecipitation, surface-plasmon resonance and mass spectrometry.

3- - Use of conditional transgenesis to study the late, non-developmental roles of pituitary transcription factors

Several pituitary transcription factors, for example Pitx1 and 2 or Pou1F1/Pit-1, for which a developmental role has been clearly established, continue to be expressed in the differentiated pituitary. However, their functional role in the developped gland is unknown. To approach this role, we are setting up a conditional gene inactivation strategy to inactivate these transcription factors specifically in the postnatal pituitary. For that, we use a new modulatable Cre recombinase, DiCre, that we have developped previously (Jullien et al., Nucl. Acid Res, 2003, 31:e131; Jullien et coll., PLoS ONE, 2007, 2:e1355), or the tetracycline-regulated system.

Highlighted Publications

The CRN2M in numbers

  • 20 Researchers
  • 19 Enseignants Chercheurs
  • 39 Technicians and Assistants
  • 3 Post-Docs
  • 5 Docs
  • 4 Master Students

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