Mutations du facteur de transcription Tpitet différenciation hypophysaire

Abstract

La différenciation cellulaire repose sur l’acquisitiond’une nouvelle identité cellulaire et donc d’unnouveau programme d’expression génique. Nousavons montré que Tpit,un facteur de transcriptionspécifiquedes cellules corticotropes et mélanotropesde l’hypophyse, est un régulateur positif dela différenciation de ces cellules, mais aussi unrégulateur négatif de la lignée gonadotrope. Outreun mécanisme de choix mutuellement exclusifslors de la différenciation, ces travaux suggèrentun modèle complet de différenciation hypophysaireà choix binaires. En accord avec l’expressionexclusive de Tpit dans les cellules corticotropes,plusieurs mutations du gène humain TPIT ont étéidentifiées chez des patients atteints d’un déficitcorticotrope 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.