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Multiple Pituitary and Ovarian Defects in Krox-24 (NGFI-A, Egr-1)-Targeted Mice

U-368, INSERM (P.T., S.S.-M., G.L., P.C.) Biologie Moléculaire du Développement Ecole Normale Supérieure 75230 Paris, France
Laboratory of Molecular Biology (G.L.) Advanced Biotechnology Center-IST Genova, Italy
URA CNRS 1414 (A.T.) Ecole Normale Supérieure 75230 Paris, France
U-159, INSERM (D.G.) Centre Paul Broca 75014 Paris, France
Institut National de la Recherche Agronomique Physiologie de la Reproduction des Mammifères Domestiques (M.-A.D.) 37380 Nouzilly, France
Laboratory of Molecular Reproductive Biology and Medicine Department of Obstetrics and Gynecology (C.V.R.) University of Louisville Health Science Center Louisville, Kentucky 40292

The zinc finger transcription factor Krox-24 (NGFI-A, Egr-1) is encoded by an immediate-early serum response gene expressed in various physiological situations and tissues. To investigate its function, we have created a null allele. Mice homozygous for the mutation have a reduced body size, and both males and females are sterile. These phenotypes were related to defects in the anterior pituitary of both sexes and in the ovary. In the pituitary, two cell lineages expressing Krox-24 are differentially affected by the mutation: somatotropes present abnormal cytological features and are reduced in number, consistent with the decreased GH content observed in these animals; in contrast gonadotropes are normal in number, but specifically fail to synthesize the ß-subunit of LH. In the ovary, LH receptor expression is prevented, indicating an involvement of Krox-24 at two levels at least of the pituitary-gonadal axis. Our data, together with the results of a previous report describing another Krox-24 mutant allele, suggest that Krox-24 may have two distinct molecular functions in the anterior pituitary: transcriptional activation of the LHß gene in gonadotropes and control of cell proliferation and/or survival in somatotropes by unknown mechanisms.

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