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This Article Full Text Full Text (PDF) [Supplemental Data] All Versions of this Article: 79/4/598    most recent biolreprod.108.068304v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Million Passe, C. M. Articles by Quirk, C. C. PubMed PubMed Citation Articles by Million Passe, C. M. Articles by Quirk, C. C. Agricola Articles by Million Passe, C. M. Articles by Quirk, C. C.

Loss of the Protein NUPR1 (p8) Leads to Delayed LHB Expression, Delayed Ovarian Maturation, and Testicular Development of a Sertoli-Cell-Only Syndrome-Like Phenotype in Mice¹

Medical Sciences Program,³ Indiana University School of Medicine, Bloomington, Indiana 47405 Interdisciplinary Graduate Program in Biochemistry⁴ and Human Biology Program,⁵ Indiana University, Bloomington, Indiana 47405 Department of Biochemistry and Molecular Biology,⁶ Indiana University School of Medicine, Terre Haute, Indiana 47809 Centre de Recherche,⁷ Institut National de la Santé Et de la Recherche Médicale (INSERM), 13288 Marseille, France

ABSTRACT

The high mobility group factor NUPR1, also known as p8 and com1, plays a role in temporal expression of the beta subunit of luteinizing hormone, LHB, during gonadotroph development. At Embryonic Day (e) 16.5, LHB is detectable in wild-type (Nupr1^+/+) but not Nupr1 knockout (Nupr1^–/–) mice. LHB is initiated by e17.5 in Nupr1^–/– mice, and expression is fully recovered by Postnatal Day (p) 2. Factors indicative of pituitary maturation, GATA2, CGA, and TSH, are not differentially expressed in Nupr1^–/– and Nupr1^+/+ embryos at e17.5. Therefore, the delay in LHB expression does not appear to result from delayed pituitary development. In addition, the role of NUPR1 in gonadotropin expression appears specific for LHB, as no difference in FSHB is observed in Nupr1^–/– and Nupr1^+/+ embryos. The gonads are also impacted by the absence of NUPR1. Ovaries of female Nupr1^–/– mice lack corpora lutea (CL) at 8 wk, an age at which CL are present in all Nupr1^+/+ littermates. Sexual maturity is recovered by 11 wk in Nupr1^–/– mice. Conversely, the testes of Nupr1^–/– males appear normal through 8 mo of age. By 10 mo, however, these mice develop a condition in which a significant number of seminiferous tubules lack germ cells, an abnormality reminiscent of human Sertoli-cell-only syndrome. NUPR1 is undetectable in Nupr1^+/+ gonadotrophs by p2 and remains absent in adulthood, but quantitative PCR analysis indicates Nupr1^+/+ adult ovaries and testes express Nupr1 mRNA. Therefore, the ovarian and testicular phenotypes may be due to the loss of NUPR1 directly at the gonads.

gonadotroph, luteinizing hormone, NUPR1, ovary, p8, pituitary, Sertoli-cell-only syndrome, testis

¹Supported by a Research Starter Grant in Pharmacology/Toxicology from the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation awarded to C.C.Q. and a Predoctoral Fellowship from the Greater Midwest Affiliate of the American Heart Association awarded to C.M.M.P.

Correspondence: ²Christine C. Quirk, Indiana University, Medical Sciences Program, 1001 East 3rd St., Bloomington, IN 47405. FAX: 812 855 4436; e-mail: cquirk{at}indiana.edu