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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Apr 1;89(7):2764–2768. doi: 10.1073/pnas.89.7.2764

Pituitary hyperplasia induced by ectopic expression of nerve growth factor.

E Borrelli 1, P E Sawchenko 1, R M Evans 1
PMCID: PMC48743  PMID: 1348359

Abstract

Nerve growth factor (NGF) cDNA was fused to the rat prolactin promoter to induce its ectopic expression in pituitary lactotrophs of transgenic mice. High-level expression of both RNA and functional protein was achieved in two pedigrees. Pituitary cells from these animals secreted biologically active NGF that was capable of inducing rapid differentiation of cocultured PC12 pheochromocytoma cells. Despite this robust expression, transgenic pituitaries failed to show any detectable increase in neuronal innervation. Unexpectedly, we observed a dramatic hyperplasia of lactotrophs resulting in pituitaries 10-100 times larger than normal. These results suggest that NGF, in addition to its previously described effects, may act as a new class of mitogen, with a potential role in oncogenesis.

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Selected References

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  1. Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
  2. Ayer-LeLievre C., Olson L., Ebendal T., Hallbök F., Persson H. Nerve growth factor mRNA and protein in the testis and epididymis of mouse and rat. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2628–2632. doi: 10.1073/pnas.85.8.2628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bar-Sagi D., Feramisco J. R. Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation. Cell. 1985 Oct;42(3):841–848. doi: 10.1016/0092-8674(85)90280-6. [DOI] [PubMed] [Google Scholar]
  4. Borrelli E., Heyman R. A., Arias C., Sawchenko P. E., Evans R. M. Transgenic mice with inducible dwarfism. Nature. 1989 Jun 15;339(6225):538–541. doi: 10.1038/339538a0. [DOI] [PubMed] [Google Scholar]
  5. Buck C. R., Martinez H. J., Black I. B., Chao M. V. Developmentally regulated expression of the nerve growth factor receptor gene in the periphery and brain. Proc Natl Acad Sci U S A. 1987 May;84(9):3060–3063. doi: 10.1073/pnas.84.9.3060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burton F. H., Hasel K. W., Bloom F. E., Sutcliffe J. G. Pituitary hyperplasia and gigantism in mice caused by a cholera toxin transgene. Nature. 1991 Mar 7;350(6313):74–77. doi: 10.1038/350074a0. [DOI] [PubMed] [Google Scholar]
  7. Edwards R. H., Rutter W. J., Hanahan D. Directed expression of NGF to pancreatic beta cells in transgenic mice leads to selective hyperinnervation of the islets. Cell. 1989 Jul 14;58(1):161–170. doi: 10.1016/0092-8674(89)90412-1. [DOI] [PubMed] [Google Scholar]
  8. Greene L. A., Tischler A. S. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2424–2428. doi: 10.1073/pnas.73.7.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hagag N., Halegoua S., Viola M. Inhibition of growth factor-induced differentiation of PC12 cells by microinjection of antibody to ras p21. Nature. 1986 Feb 20;319(6055):680–682. doi: 10.1038/319680a0. [DOI] [PubMed] [Google Scholar]
  10. Herrup K., Thoenen H. Properties of the nerve growth factor receptor of a clonal line of rat pheochromocytoma (PC12) cells. Exp Cell Res. 1979 Jun;121(1):71–78. doi: 10.1016/0014-4827(79)90445-2. [DOI] [PubMed] [Google Scholar]
  11. Korsching S., Auburger G., Heumann R., Scott J., Thoenen H. Levels of nerve growth factor and its mRNA in the central nervous system of the rat correlate with cholinergic innervation. EMBO J. 1985 Jun;4(6):1389–1393. doi: 10.1002/j.1460-2075.1985.tb03791.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kruijer W., Schubert D., Verma I. M. Induction of the proto-oncogene fos by nerve growth factor. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7330–7334. doi: 10.1073/pnas.82.21.7330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Levi-Montalcini R., Angeletti P. U. Nerve growth factor. Physiol Rev. 1968 Jul;48(3):534–569. doi: 10.1152/physrev.1968.48.3.534. [DOI] [PubMed] [Google Scholar]
  14. Lira S. A., Crenshaw E. B., 3rd, Glass C. K., Swanson L. W., Rosenfeld M. G. Identification of rat growth hormone genomic sequences targeting pituitary expression in transgenic mice. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4755–4759. doi: 10.1073/pnas.85.13.4755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Manthorpe M., Skaper S. D., Williams L. R., Varon S. Purification of adult rat sciatic nerve ciliary neuronotrophic factor. Brain Res. 1986 Mar 5;367(1-2):282–286. doi: 10.1016/0006-8993(86)91603-3. [DOI] [PubMed] [Google Scholar]
  16. Meinkoth J., Wahl G. Hybridization of nucleic acids immobilized on solid supports. Anal Biochem. 1984 May 1;138(2):267–284. doi: 10.1016/0003-2697(84)90808-x. [DOI] [PubMed] [Google Scholar]
  17. Nelson C., Crenshaw E. B., 3rd, Franco R., Lira S. A., Albert V. R., Evans R. M., Rosenfeld M. G. Discrete cis-active genomic sequences dictate the pituitary cell type-specific expression of rat prolactin and growth hormone genes. Nature. 1986 Aug 7;322(6079):557–562. doi: 10.1038/322557a0. [DOI] [PubMed] [Google Scholar]
  18. Sawchenko P. E., Swanson L. W., Grzanna R., Howe P. R., Bloom S. R., Polak J. M. Colocalization of neuropeptide Y immunoreactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus. J Comp Neurol. 1985 Nov 8;241(2):138–153. doi: 10.1002/cne.902410203. [DOI] [PubMed] [Google Scholar]
  19. Scott J., Selby M., Urdea M., Quiroga M., Bell G. I., Rutter W. J. Isolation and nucleotide sequence of a cDNA encoding the precursor of mouse nerve growth factor. Nature. 1983 Apr 7;302(5908):538–540. doi: 10.1038/302538a0. [DOI] [PubMed] [Google Scholar]
  20. Thoenen H., Barde Y. A. Physiology of nerve growth factor. Physiol Rev. 1980 Oct;60(4):1284–1335. doi: 10.1152/physrev.1980.60.4.1284. [DOI] [PubMed] [Google Scholar]
  21. Vale W., Vaughan J., Yamamoto G., Bruhn T., Douglas C., Dalton D., Rivier C., Rivier J. Assay of corticotropin releasing factor. Methods Enzymol. 1983;103:565–577. doi: 10.1016/s0076-6879(83)03040-2. [DOI] [PubMed] [Google Scholar]
  22. Weinberger C., Hollenberg S. M., Ong E. S., Harmon J. M., Brower S. T., Cidlowski J., Thompson E. B., Rosenfeld M. G., Evans R. M. Identification of human glucocorticoid receptor complementary DNA clones by epitope selection. Science. 1985 May 10;228(4700):740–742. doi: 10.1126/science.2581314. [DOI] [PubMed] [Google Scholar]

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