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

Abstract

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.

Tbx4is not required for hindlimb identity or post-bud hindlimb outgrowth

“…Sall4 can drive Fgf10 limb expression and activates an Fgf10 reporter synergistically with either Tbx4 or Tbx5, but Sall4 expression is dependent on T-box regulation and is a poor candidate for an independent regulator of Fgf10 (Harvey and Logan, 2006;Koshiba-Takeuchi et al, 2006). Pitx transcription factors are known to interact directly with T-box genes (Lamolet et al, 2001), and double mutation of Pitx1 and Pitx2 produces a phenotype very similar to the post-initiation loss of Tbx4 (Marcil et al, 2003), but loss of these genes also dramatically downregulates Tbx4, suggesting that the observed phenocopy is due to the downstream loss of Tbx4. A better candidate is Snai1, which is expressed in the hindlimb at a relatively earlier stage than in the forelimb, as predicted by our model, and appears to be upstream of Fgf10 (Isaac et al, 2000).…”

Expression of the Wdr9 gene and protein products during mouse development

“…1 region b). Antiserum recognizing both WDR9 isoforms was purified by affinity chromatography over a GST-WDR9 (fusion protein of GST with the same murine WDR9 residues as above) column as previously described (Lamolet et al, 2001). Eluted immunoglobulin G was subsequently dialyzed and concentrated with a Millipore Ultrafree centrifugal filter.…”

Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing’s disease and subclinical Cushing’s disease

“…In the anterior lobe of the pituitary gland, POMC gene is expressed in ACTH-producing cells, and its expression is regulated by various transcription factors, such as Tpit and Nur77. Tpit is exclusively expressed in pituitary POMC-expressing lineages, and is essential for cellspecific transcription of the POMC gene [16]. Maria et al reported that Tpit and Nur77 cooperatively induce POMC gene expression [17].…”