Tbx19, a tissue-selective regulator of POMC gene expression - PubMed (original) (raw)

Tbx19, a tissue-selective regulator of POMC gene expression

J Liu et al. Proc Natl Acad Sci U S A. 2001.

Abstract

Pituitary cell types arise in a temporally and spatially specific fashion, in response to combinatorial actions of transcription factors induced by transient signaling gradients. The critical transcriptional determinants of the two pituitary cell types that express the pro-opiomelanocortin (POMC) gene, the anterior lobe corticotropes, producing adrenocorticotropin, and the intermediate lobe melanotropes, producing melanocyte-stimulating hormone (MSH alpha), have remained unknown. Here, we report that a member of the T-box gene family, Tbx19, which is expressed only in the rostral ventral diencephalon and pituitary gland, commencing on e11.5, marks pituitary cells that will subsequently express the POMC gene and is capable of altering progression of ventral cell types and inducing adrenocorticotropin in rostral tip cells. It is suggested that Tbx19, depending on the presence of synergizing transcription factors, can activate POMC gene expression and repress the alpha glycoprotein subunit and thyroid-stimulating hormone beta promoters.

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Figures

Figure 1

Figure 1

Expression of Tbx19 in pituitary development. (A) Nucleotide sequence of murine Tbx19 cDNA ORF predicts a 446-aa gene product containing a T-box (boxed). Reverse lettering on amino acid 147 indicates the site of mutation for Fig. 5 (N → T). (B) In situ hybridization using Tbx19 or POMC probes demonstrates expression of Tbx19 on e11.5 (open arrowhead) in the caudoventral aspect of developing anterior pituitary, followed by expression of POMC in Tbx19-expressing cells by e12–e12.5. Tbx19 expression is apparently restricted to POMC lineages. In ventral diencephalon, Tbx19 (closed arrowhead) is expressed from ≈e10.5, late in the arcuate and paraventricular nucleus, but is not expressed in the lateral regions of the arcuate nucleus where POMC is expressed (closed arrowhead).

Figure 2

Figure 2

BETA2/NeuroD1 is not alone required for pituitary development. (A) Expression patterns of Mash-1 and BETA2/Neuro D1 showing initial ventral expression, and continued expression of MASH-1 on POMC lineages, but with extinction of BETA2 by e16.5. (B) In situ hybridization analysis of e17.5 pituitary, using the indicated cDNA probes, showing normal development of BETA2 (−/−) mice.

Figure 3

Figure 3

Cell type development in the hypoplastic pituitary of Pitx1/Tbx19 transgenic mice. (A) Representative section (e14.5) of a pituitary expressing HA-tagged Tbx19, under control of the 8-kb Pitx1 promoter. (B) The pituitary exhibits no alteration of ACTH-expression but decreased numbers of αGSU+ and Pit-1+ cells.

Figure 4

Figure 4

Phenotype of the αGSU/Tbx19 mouse pituitary gland. (A) The expression of HA-tagged Tbx19 follows the normal pattern of αGSU-expression, but levels of αGSU are markedly decreased, whereas ACTH is now expressed in virtually all rostral tip cells, no change in expression of ventral anterior pituitary. (B) Double label immunohistochemistry, showing a decreased TSHβ expression in αGSU/Tbx19-expressing cells of the Pit-1 lineage, but with no coexpression of POMC and TSHβ. (C) A Tbx19 mutant incapable of specific binding to cognate DNA elements no longer induced rostral tip expression of POMC or decreased αGSU gene expression in ventral pituitary.

Figure 5

Figure 5

Tbx19 can repress the αGSU promoter in transient transfection assays. (A) Effects of cytomegalovirus/Tbx19 and cytomegalovirus/Pitx1 on expression of a POMC (−480 to +64) luciferase fusion gene in HeLa cells. (B) Effects of mutation of the consensus T-box half site in the POMC promoter on expression in AtT20 corticotropes. (C) Effects of cytomegalovirus/Tbx19 on αGSU expression, and effects of Tbx19, on Pitx1- or Lhx3-induced expression of the αGSU promoter (−400 to +34) in HeLa cells; results are an average of duplicates differing by <5%.

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