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.

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.[Keywords: Repression; nuclear receptor; Swi/Snf; pituitary tumors; POMC; Cushing] Supplemental material is available at http://www.genesdev.org.

The predominance of high molecular weight PRL, or macroprolactinemia, has long been known in hyperprolactinemic patients with maintained fertility. Among 1,106 consecutive patients investigated for hyperprolactinemia in our center over a 10-yr period, serum PRL chromatography was performed in 368 cases because of discordant clinical, biological, or neuroradiological findings. We prospectively studied the 106 patients with macroprolactinemia (96 women, 6 men, 4 children) and compared them with the 262 hyperprolactinemic patients with a normal PRL elution pattern. We concluded the following: 1) the incidence of macroprolactinemia in our hyperprolactinemic population was at least 10%; 2) despite preserved fertility with uneventful pregnancies, some of the usual symptoms of hyperprolactinemia were present; 3) mean PRL values were 61 +/- 66 microg/liter (range, 20-663) and exceeded 100 microg/liter in 8.5% of patients; 4) PRL levels usually remained stable over time; 5) on dopaminergic therapy, PRL returned to normal in 21 of 45 treated patients; 6) during follow-up of 7 pregnancies, PRL increased to supraphysiological levels in 5; and 7) pituitary magnetic resonance imaging was normal in 78% of patients or revealed diverse pituitary lesions, including adenomas (n = 5). A diagnostic method for macroprolactinemia should be available to all centers to avoid unnecessary hormonal or radiological investigations and treatments.

Tpit is a highly cell-restricted transcription factor that is required for expression of the pro-opiomelanocortin (POMC) gene and for terminal differentiation of the pituitary corticotroph lineage. Its exclusive expression in pituitary POMC-expressing cells has suggested that its mutation may cause isolated deficiency of pituitary adrenocorticotropin (ACTH). We now show that Tpit-deficient mice constitute a model of isolated ACTH deficiency (IAD) that is very similar to human IAD patients carrying TPIT gene mutations. Through genetic analysis of a panel of IAD patients, we show that TPIT gene mutations are associated at high frequency with early onset IAD, but not with juvenile forms of this deficiency. We identified seven different TPIT mutations, including nonsense, missense, point deletion, and a genomic deletion. This work defines congenital early onset IAD as a relatively homogeneous clinical entity caused by recessive transmission of loss-of-function mutations in the TPIT gene.

Mutation of PROP1 gene remains the first to be looked for, and POU1F1 mutations should be sought in GH deficiency and TSH deficiency postpubertal population without extrapituitary malformations. Identification of gene defects allows early treatment of any deficit and prevention of their potentially fatal consequences. Genotyping appears highly beneficial at an individual and familial level.