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Regulation of Prolactin, GH, and Pit-1 Gene Expression in Anterior Pituitary by Pitx2: An Approach Using Pitx2 Mutants

Laboratoire Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Centre National de la Recherche Scientifique, Université de la Méditerranée, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Marseille 13916, France

Address all correspondence and requests for reprints to: Dr. Isabelle Pellegrini, Laboratoire Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Centre National de la Recherche Scientifique-Université de la Méditerranée, Institut Fédératif Jean Roche, Faculté de Médecine Nord, Bd. P. Dramard, 13916 Marseille cedex 20, France. E-mail: . pellegrini.i{at}jean-roche.univ-mrs.fr

The transcription factor Pitx2 is required for the morphogenesis of anterior structures such as the eye, teeth, and anterior pituitary. We investigated the functional properties of Pitx2 missense mutants previously reported in Axenfeld-Rieger syndrome, using reporter genes under the control of pituitary target gene [human (h)PRL, hGH, hPit-1] promoters transfected in nonpituitary and pituitary cell lines. The five mutants appeared to be transcriptionally defective despite conserved DNA-binding in CV1 cells. In addition, one mutation, R91P, almost completely blocked the wt-Pitx2-induced activation of the target promoters, prevented the Pitx2/Pit-1 synergistic activation of the hPRL promoter, and was able to counteract the Pitx1-driven transactivation effects. The dominant negative properties of this mutant were further established in cells endogenously expressing Pitx2 because transfection of R91P in GH4C1 somatolactotroph cells resulted in a dose-dependent inhibition of basal activities of the pituitary promoters. These results, which show that Pitx2 mutants are defective in activating pituitary target genes, confirm the critical role of this homeodomain factor in the differentiated functions of the pituitary somatolactotroph cells. Furthermore, these results might form the basis for future experiments because dominant negative forms of Pitx2 such as R91P might provide instructive tools to further delineate the detailed mechanisms mediating Pitx2 functions in cell proliferation and differentiation.

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