Bases moléculaires des hypopituitarismes congénitaux

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Mutations du facteur de transcription Tpit et différenciation hypophysaire

La différenciation cellulaire repose sur l’acquisition d’une nouvelle identité cellulaire et donc d’un nouveau programme d’expression génique. Nous avons montré que Tpit, un facteur de transcription spécifique des cellules corticotropes et mélanotropes de l’hypophyse, est un régulateur positif de la différenciation de ces cellules, mais aussi un régulateur négatif de la lignée gonadotrope. Outre un mécanisme de choix mutuellement exclusifs lors de la différenciation, ces travaux suggèrent un modèle complet de différenciation hypophysaire à choix binaires. En accord avec l’expression exclusive de Tpit dans les cellules corticotropes, plusieurs mutations du gène humain TPIT ont été identifiées chez des patients atteints d’un déficit corticotrope isolé congénital.Pituitary hormone-producing cells differentiate sequentially from a common epithelial primordium, Rathke’s pouch, under the combinatorial action of a subset of tissue- and cell-restricted transcription factors. Some factors have been implicated in early events of pituitary induction and morphogenesis while other factors like Pit-1 and SF-1 have been associated with differentiation of particular lineages. In POMC-expressing cells, Pitx1, NeuroD1 and Tpit were shown to be important for cell specific transcription of the POMC gene. Since Tpit is exclusively expressed in pituitary POMC-expressing lineages, the corticotrophs and melanotrophs, we investigated the TPIT gene coding sequences in 17 patients presenting with congenital isolated ACTH deficiency (IAD). We demonstrated that human TPIT gene mutations cause a neonatal onset form of IAD (8/11), but not juvenile forms of this deficiency (0/6). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. To assess the importance of Tpit in pituitary differentiation and function, we produced Tpit-null mice. Concordant with the human phenotype, Tpit-null mice have IAD : plasma ACTH is greatly reduced in these mice, their plasma corticosterone is undetectable and the adrenals are hypoplastic. Analysis of the pituitary in Tpit-null mice revealed multiple roles of this factor in cell differentiation. First, Tpit is a positive regulator for POMC cell differentiation. Tpit is also a negative regulator of the pituitary gonadotroph fate. Thus, Tpit operates as a molecular switch to orient differentiation of a common precursor towards either POMC or gonadotroph fate. A binary choice model of pituitary cell differentiation is presented

Tpit determines alternate fates during pituitary cell differentiation

The T-box transcription factor Tpit was identified as a cell-specific factor for expression of the pituitary proopiomelanocortin (POMC) gene. Expression of this factor is exclusively restricted to the pituitary POMC-expressing lineages, the corticotrophs and melanotrophs. We have now determined the role of this factor in pituitary cell differentiation. Tpit is a positive regulator for late POMC cell differentiation and POMC expression, but it is not essential for lineage commitment. The pituitary intermediate lobe normally contains only Tpit-expressing melanotrophs. Inactivation of the Tpit gene results in almost complete loss of POMC-expressing cells in this tissue, which now has a large number of gonadotrophs and a few clusters of Pit-1-independent thyrotrophs. The role of Tpit as a negative regulator of gonadotroph differentiation was confirmed in transgenic gain-of-function experiments. One mechanism to account for the negative role of Tpit in differentiation may be trans-repression between Tpit and the gonadotroph-restricted factor SF1. These data suggest that antagonism between Tpit and SF1 may play a role in establishment of POMC and gonadotroph lineages and that these lineages may arise from common precursors

Facteurs prédictifs du devenir des patients opérés d'une maladie de Cushing

Objectifs: Déterminer le devenir à long terme de 55 patients avec une maladie de Cushing, suivis en moyenne 26+/-3.8 mois. Conclusions: Les adénomes corticotropes sont le plus souvent des microadénomes latéraux, envahissant les structures adjacentes dans 30% des cas. Le traitement de première intention est la microchirurgie par voie transphenoidale, permettant une guérison dans 76% des cas. Malgré un taux bas d'échecs immédiats, (11%) les récidives à moyen et long terme (13%) ne sont pas négligeables. Ceci est probablement lié à la fréquence de l'invasion locale, mise en évidence par les données neuroradiologiques et chirurgicales. Sur les 14 paramètres analysées, trois critères peuvent et être considérés comme prédictifs du devenir des patients opérés d'une maladie de Cushing: les signes d'invasion tumorale locale sur IRM ou visualisés par le neurochirurgien et les taux postopératoires immédiats de cortisol. Cependant ces paramètres son t indicatifs et ne dispensent pas du suivi annuel des patients, nécessaire afin de dépister les éventuelles récidives pouvant bénéficier d'une radiothérapie complémentaire focalisée ou non

Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease

Negative feedback regulation of the proopiomelanocortin (POMC) gene by the glucocorticoid (Gc) receptor (GR) is a critical feature of the hypothalamo–pituitary–adrenal axis, and it is in part exerted by trans-repression between GR and the orphan nuclear receptors related to NGFI-B. We now show that Brg1, the ATPase subunit of the Swi/Snf complex, is essential for this trans-repression and that Brg1 is required in vivo to stabilize interactions between GR and NGFI-B as well as between GR and HDAC2. Whereas Brg1 is constitutively present at the POMC promoter, recruitment of GR and HDAC2 is ligand-dependent and results in histone H4 deacetylation of the POMC locus. In addition, GR-dependent repression inhibits promoter clearance by RNA polymerase II. Thus, corecruitment of repressor and activator at the promoter and chromatin modification jointly contribute to trans-repression initiated by direct interactions between GR and NGFI-B. Loss of Brg1 or HDAC2 should therefore produce Gc resistance, and we show that ∼50% of Gc-resistant human and dog corticotroph adenomas, which are the hallmark of Cushing disease, are deficient in nuclear expression of either protein. In addition to providing a molecular basis for Gc resistance, these deficiencies may also contribute to the tumorigenic process