Mutations du facteur de transcription Tpit et différenciation hypophysaire Tpit mutations reveal a new model of pituitary differentiation and account for isolated ACTH deficiency

Résumé

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.

Summary

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.