Anne-Marie Pulichino

A Pituitary Cell-Restricted T Box Factor, Tpit, Activates POMC Transcription in Cooperation with Pitx Homeoproteins

The pituitary gland has provided unique insight into molecular mechanisms and regulatory factors controlling both differentiation and gene transcription. We identified Tpit, a novel T box factor only present in the two pituitary POMC-expressing lineages, the corticotrophs and melanotrophs, and apparently in no other tissue, including hypothalamic POMC neurons. In pituitary cells, Tpit activation of POMC gene transcription requires cooperation with Pitx1, the two factors binding to contiguous sites within the same regulatory element. In gain-of-function experiments, Tpit induces POMC expression in undifferentiated pituitary cells, indicating that it can initiate differentiation into POMC-expressing lineages. TPIT gene mutations were found in patients with isolated deficiency of pituitary POMC-derived ACTH, in support of an essential role of Tpit for differentiation of the pituitary POMC lineage.

Tpit‐/‐NeuroD1‐/‐ Mice Reveal Novel Aspects of Corticotroph Development

The hypothalamus-pituitary-adrenal (HPA) axis plays a primordial role in the control of homeostasis. Pituitary corticotroph cells produce POMC that is cleaved into ACTH. ACTH is an important regulator of HPA which stimulates production of glucocorticoids by the adrenals. The pituitary differentiation process is under the combined action of tissueand cell-restricted transcription factors. In corticotrophs, Tpit and NeuroD1 are both cell-specific activators of POMC expression. Their expression precedes closely that of POMC suggesting a role in differentiation of the lineage. We generated Tpit-/mice in which most Tpit coding sequences were replaced by a b-galactosidase gene. These mice are deficient in POMC-expressing cells consistent with a positive action of Tpit on these lineages; Tpit was also shown to be a negative regulator of the gonadotroph fate. However, the developing anterior pituitary of Tpit-/mice has a normal number of b-galactosidase and NeuroD1-positive cells, indicating that initiation of corticotroph differentiation is not prevented in the absence of Tpit. Corticotroph differentiation is delayed in NeuroD1-/mice but this is not resulting from

Transcriptional regulation of pituitary gland development: binary choices for cell differentiation

Purpose of reviewThe first model of simple relations among all pituitary lineages has been proposed in the past year. This has been possible through identification of transcription factors that control differentiation of pituitary lineages. This review will summarize current knowledge of the role of transcription factors in the control of pituitary cell differentiation and also in early organogenesis of the pituitary gland. Recent findingsThe T-box transcription factor Tpit has dual roles as positive regulator of the corticotroph and melanotroph lineages and as negative regulator of the gonadotroph lineage. This has suggested a common origin for these lineages and set them apart from the other lineages that were previously shown to be Pit1-dependent. These findings now allow all pituitary lineages to be integrated in a scheme of simple relations in which cell fate decisions are made through successive binary choices. Thus, various transcription factors control the processes of early pituitary patterning and organogenesis, of cell proliferation, and of cell differentiation. SummaryDiscovery of transcription factors responsible for pituitary cell differentiation and organogenesis has had an immediate impact on understanding and diagnosis of pituitary hormone deficiencies. Thus, combined pituitary hormone deficiencies have been associated with mutations in transcription factor coding genes that control organogenesis or multiple lineages, whereas isolated hormone deficiencies are often caused by transcription factors controlling late differentiation. The description of a simple model for pituitary cell differentiation also highlights regulatory mechanisms that remain to be identified to fully understand pituitary development and pituitary pathologies.

A neonatal form of isolated ACTH deficiency frequently associated with Tpit gene mutations.

Tpit is a T-box transcription factor involved in terminal differentiation of the pituitary POMC-expressing cells. We previously demonstrated that human and mice mutations of the highly cortico/melanotroph specific transcription factor gene Tpit cause a neonatal onset form of congenital isolated ACTH deficiency (IAD). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. This clinical entity was not previously well characterized because of the small number of published cases. We investigated the Tpit gene coding sequences in 28 patients (22 unrelated families) presenting with neonatal onset IAD. We found a Tpit mutation in 17/28 patients (61%). We identified 10 different Tpit mutations with a high frequency site in exon 6, which was found in 5 unrelated families. All patients were homozygous or compound heterozygotes for Tpit mutations, and their unaffected parents were all heterozygous carriers, confirming the recessive mode of transmission. It is noteworthy that five compound heterozygotes involving different mutations were identified. We compared the clinical and biological phenotype of the 17 IAD patients carrying a Tpit mutation with the 11 remaining IAD patients and we didn’t find any