Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone β-subunit gene regulatory region in transgenic mice

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  • Additional Information
    • Affiliation:
      a Departments of Reproductive Medicine and Neuroscience, University of California, 2057 Cellular and Molecular Medicine, East 9500 Gilman Drive, San Diego, La Jolla, CA 92093-0674, USA
      b Department of Biochemistry, North Carolina State University, Raleigh, NC 27695, USA
    • Keywords:
      Follicle-stimulating hormone
      Gonadotrope
      T antigen
      Tumors
      Transgenic mice
    • Abstract:
      Targeted tumorigenesis in transgenic mice has been a powerful tool for the study of gene expression and oncogenesis, as well as for the production of differentiated immortal cell lines from rare cell types. Follicle-stimulating hormone (FSH) is secreted by the gonadotrope cells of the anterior pituitary gland and plays a pivotal role in mammalian reproduction. Here we have used the regulatory region of the ovine FSHβ gene to direct expression of the SV40 T antigen oncogene to gonadotrope cells in the pituitary of transgenic mice. Two of five transgenic mouse lines bearing this fusion gene rapidly developed pituitary tumors, with appearance of adenomatous foci as early as 6 weeks of age, resulting in death by 12 weeks of age in both genders. Histologic examination of tumor development over time revealed that increases in cell proliferation and dysplasia were accompanied by decreases in synthesis of pituitary hormones, indicating dedifferentiation of the pituitary cells. Histological features observed in these tumors were in agreement with this rapid transformation of cell phenotype. Tumors were multifocal in origin, and the most highly transformed cell types observed consisted of giant pale basophilic cells with enormous hyperploid nuclei associated with infiltrating neuronal-like cells, which were very abundant at later stages of tumor development. Mitotic indices were much higher in transgenic than wild-type pituitaries, as expected. Morphologic analysis of the gonads of these transgenic mice showed no major developmental differences, as compared to wild-type littermates, however the length of the seminiferous tubules in transgenic males was greater than age-matched wild-type animals. Despite this phenotype difference, both genders were fertile, with normal sperm development observed in males and normal estrous cycle stages in females. Moreover, while 8–10-week-old transgenic males had much lower blood levels of FSH than littermates, transgenic female FSH levels were the same as those of wild-type females. These animals offer a unique and potentially useful model of organ-specific tumorigenesis, where a multistage pathway of tumor development is evident, both histologically and temporally. Study of such models will advance our knowledge on the physiological and molecular mechanisms involved in gene expression as well as tumor formation.
    • ISSN:
      0303-7207
    • Accession Number:
      10.1016/S0303-7207(02)00430-6
    • Accession Number:
      S0303720702004306
    • Copyright:
      Copyright @ 2003 Elsevier Science Ireland Ltd All rights reserved.
  • Citations
    • ABNT:
      PERNASETTI, F. et al. Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone β-subunit gene regulatory region in transgenic mice. Molecular and Cellular Endocrinology, [s. l.], v. 203, n. 1, p. 169–183, 2003. DOI 10.1016/S0303-7207(02)00430-6. Disponível em: http://widgets.ebscohost.com/prod/customlink/proxify/proxify.php?count=1&encode=0&proxy=&find_1=&replace_1=&target=http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edselp&AN=S0303720702004306&authtype=sso&custid=s5834912. Acesso em: 4 ago. 2020.
    • AMA:
      Pernasetti F, Spady TJ, Hall SB, et al. Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone β-subunit gene regulatory region in transgenic mice. Molecular and Cellular Endocrinology. 2003;203(1):169-183. doi:10.1016/S0303-7207(02)00430-6.
    • AMA11:
      Pernasetti F, Spady TJ, Hall SB, et al. Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone β-subunit gene regulatory region in transgenic mice. Molecular and Cellular Endocrinology. 2003;203(1):169-183. doi:10.1016/S0303-7207(02)00430-6
    • APA:
      Pernasetti, F., Spady, T. J., Hall, S. B., Rosenberg, S. B., Givens, M. L., Anderson, S., Paulus, M., Miller, W. L., & Mellon, P. L. (2003). Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone β-subunit gene regulatory region in transgenic mice. Molecular and Cellular Endocrinology, 203(1), 169–183. https://doi.org/10.1016/S0303-7207(02)00430-6
    • Chicago/Turabian: Author-Date:
      Pernasetti, Flavia, Thomas J. Spady, Sara B. Hall, Suzanne B. Rosenberg, Marjory L. Givens, Scott Anderson, Michelle Paulus, William L. Miller, and Pamela L. Mellon. 2003. “Pituitary Tumorigenesis Targeted by the Ovine Follicle-Stimulating Hormone β-Subunit Gene Regulatory Region in Transgenic Mice.” Molecular and Cellular Endocrinology 203 (1): 169–83. doi:10.1016/S0303-7207(02)00430-6.
    • Harvard:
      Pernasetti, F. et al. (2003) ‘Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone β-subunit gene regulatory region in transgenic mice’, Molecular and Cellular Endocrinology, 203(1), pp. 169–183. doi: 10.1016/S0303-7207(02)00430-6.
    • Harvard: Australian:
      Pernasetti, F, Spady, TJ, Hall, SB, Rosenberg, SB, Givens, ML, Anderson, S, Paulus, M, Miller, WL & Mellon, PL 2003, ‘Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone β-subunit gene regulatory region in transgenic mice’, Molecular and Cellular Endocrinology, vol. 203, no. 1, pp. 169–183, viewed 4 August 2020, .
    • MLA:
      Pernasetti, Flavia, et al. “Pituitary Tumorigenesis Targeted by the Ovine Follicle-Stimulating Hormone β-Subunit Gene Regulatory Region in Transgenic Mice.” Molecular and Cellular Endocrinology, vol. 203, no. 1, Jan. 2003, pp. 169–183. EBSCOhost, doi:10.1016/S0303-7207(02)00430-6.
    • Chicago/Turabian: Humanities:
      Pernasetti, Flavia, Thomas J. Spady, Sara B. Hall, Suzanne B. Rosenberg, Marjory L. Givens, Scott Anderson, Michelle Paulus, William L. Miller, and Pamela L. Mellon. “Pituitary Tumorigenesis Targeted by the Ovine Follicle-Stimulating Hormone β-Subunit Gene Regulatory Region in Transgenic Mice.” Molecular and Cellular Endocrinology 203, no. 1 (January 1, 2003): 169–83. doi:10.1016/S0303-7207(02)00430-6.
    • Vancouver/ICMJE:
      Pernasetti F, Spady TJ, Hall SB, Rosenberg SB, Givens ML, Anderson S, et al. Pituitary tumorigenesis targeted by the ovine follicle-stimulating hormone β-subunit gene regulatory region in transgenic mice. Molecular and Cellular Endocrinology [Internet]. 2003 Jan 1 [cited 2020 Aug 4];203(1):169–83. Available from: http://widgets.ebscohost.com/prod/customlink/proxify/proxify.php?count=1&encode=0&proxy=&find_1=&replace_1=&target=http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edselp&AN=S0303720702004306&authtype=sso&custid=s5834912