The homeobox repressor Hesx1, expressed throughout Rathke's pouch and required for normal pituitary development, has been implicated in anterior pituitary pathogenesis in man. Prolonged expression of Hesx1 delays the appearance of anterior pituitary terminal differentiation markers in mice, particularly the gonadotroph hormones. We tested if Hesx1 could modulate gonadotrophin gene expression directly, and found that Hesx1 repressed both common alpha subunit (alpha GSU) and luteinising hormone beta-subunit (LH beta) gene promoters. Repression mapped to the Pitx1 homeodomain protein transactivation site in the proximal alpha GSU promoter, but did not map to the equivalent site on LH beta. Hesx1 repression of the alpha GSU Pitx1 site was overridden by co-transfection of Pitx1. In contrast, Hesx1 antagonised Pitx1 transactivation of LH beta in a dose-dependent manner. This was due to monomeric binding of Hesx1 on alpha GSU and homodimerisation on LH beta. The homodimerisation site comprises the Pitx1 DNA binding site and a proximal binding site, and mutation of either inhibited homodimer formation. Conversion of the LH beta Pitx1 DNA binding site to an alpha GSU-type did not promote homodimer formation, arguing that Hesx1 has pronounced site selectivity. Furthermore, mutation of the proximal half of the homodimerisation site blocked Hesx1 antagonisation of Pitx1 transactivation. We conclude that Hesx1 monomers repress gene expression, and homodimers block specific transactivation sites.

This article has been cited by other articles:

				S. Maudsley, Z. Naor, D. Bonfil, L. Davidson, D. Karali, A. J. Pawson, R. Larder, C. Pope, N. Nelson, R. P. Millar, et al. Proline-Rich Tyrosine Kinase 2 Mediates Gonadotropin-Releasing Hormone Signaling to a Specific Extracellularly Regulated Kinase-Sensitive Transcriptional Locus in the Luteinizing Hormone {beta}-Subunit Gene Mol. Endocrinol., May 1, 2007; 21(5): 1216 - 1233. [Abstract] [Full Text] [PDF]

				Z. Naor, H. N. Jabbour, M. Naidich, A. J. Pawson, K. Morgan, S. Battersby, M. R. Millar, P. Brown, and R. P. Millar Reciprocal Cross Talk between Gonadotropin-Releasing Hormone (GnRH) and Prostaglandin Receptors Regulates GnRH Receptor Expression and Differential Gonadotropin Secretion Mol. Endocrinol., February 1, 2007; 21(2): 524 - 537. [Abstract] [Full Text] [PDF]

				R. Larder, D. Karali, N. Nelson, and P. Brown Fanconi Anemia a Is a Nucleocytoplasmic Shuttling Molecule Required for Gonadotropin-Releasing Hormone (GnRH) Transduction of the GnRH Receptor Endocrinology, December 1, 2006; 147(12): 5676 - 5689. [Abstract] [Full Text] [PDF]

				R. N. Cohen, L. E. Cohen, D. Botero, C. Yu, A. Sagar, M. Jurkiewicz, and S. Radovick Enhanced Repression by HESX1 as a Cause of Hypopituitarism and Septooptic Dysplasia J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4832 - 4839. [Abstract] [Full Text] [PDF]