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. 1989 Aug;86(15):5873–5877. doi: 10.1073/pnas.86.15.5873

Cardiac and neurological abnormalities in v-fps transgenic mice.

S P Yee 1, D Mock 1, V Maltby 1, M Silver 1, J Rossant 1, A Bernstein 1, T Pawson 1
PMCID: PMC297733  PMID: 2788278

Abstract

Transgenic mice that widely express the v-fps protein-tyrosine kinase develop several independent pathological conditions, in addition to a high tumor incidence. v-fps expression and protein-tyrosine kinase activity in the heart were directly correlated with cardiac enlargement. This cardiomegaly was accompanied by severe myocardial and endocardial damage, which was concentrated in the left ventricular wall, and characterized by a progressive atrophy and necrosis of cardiac muscle fibers with concomitant fibrosis. This pathology was associated with congestive heart failure. Mice from five lines developed a marked trembling, correlated with expression of the v-fps transgene in the brain, and two lines showed a striking bilateral enlargement of the trigeminal nerves. Unlike tumor formation, these cardiac and neurological phenotypes were evident shortly after birth and showed 100% penetrance. The pleiotropic effects of the v-fps transgene suggest the involvement of protein-tyrosine kinases in mammalian neural development and cardiac function.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alpert S., Hanahan D., Teitelman G. Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell. 1988 Apr 22;53(2):295–308. doi: 10.1016/0092-8674(88)90391-1. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Baroldi G. Different types of myocardial necrosis in coronary heart disease: a pathophysiologic review of their functional significance. Am Heart J. 1975 Jun;89(6):742–752. doi: 10.1016/0002-8703(75)90189-1. [DOI] [PubMed] [Google Scholar]
  4. Bautch V. L., Toda S., Hassell J. A., Hanahan D. Endothelial cell tumors develop in transgenic mice carrying polyoma virus middle T oncogene. Cell. 1987 Nov 20;51(4):529–537. doi: 10.1016/0092-8674(87)90122-x. [DOI] [PubMed] [Google Scholar]
  5. Behringer R. R., Hammer R. E., Brinster R. L., Palmiter R. D., Townes T. M. Two 3' sequences direct adult erythroid-specific expression of human beta-globin genes in transgenic mice. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7056–7060. doi: 10.1073/pnas.84.20.7056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Behringer R. R., Peschon J. J., Messing A., Gartside C. L., Hauschka S. D., Palmiter R. D., Brinster R. L. Heart and bone tumors in transgenic mice. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2648–2652. doi: 10.1073/pnas.85.8.2648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Edwards A. M., Arquint M., Braun P. E., Roder J. C., Dunn R. J., Pawson T., Bell J. C. Myelin-associated glycoprotein, a cell adhesion molecule of oligodendrocytes, is phosphorylated in brain. Mol Cell Biol. 1988 Jun;8(6):2655–2658. doi: 10.1128/mcb.8.6.2655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Field L. J. Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice. Science. 1988 Feb 26;239(4843):1029–1033. doi: 10.1126/science.2964082. [DOI] [PubMed] [Google Scholar]
  9. Grosveld F., van Assendelft G. B., Greaves D. R., Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987 Dec 24;51(6):975–985. doi: 10.1016/0092-8674(87)90584-8. [DOI] [PubMed] [Google Scholar]
  10. Hopfield J. F., Tank D. W., Greengard P., Huganir R. L. Functional modulation of the nicotinic acetylcholine receptor by tyrosine phosphorylation. Nature. 1988 Dec 15;336(6200):677–680. doi: 10.1038/336677a0. [DOI] [PubMed] [Google Scholar]
  11. Hunter T., Cooper J. A. Protein-tyrosine kinases. Annu Rev Biochem. 1985;54:897–930. doi: 10.1146/annurev.bi.54.070185.004341. [DOI] [PubMed] [Google Scholar]
  12. Jaenisch R. Transgenic animals. Science. 1988 Jun 10;240(4858):1468–1474. doi: 10.1126/science.3287623. [DOI] [PubMed] [Google Scholar]
  13. Letwin K., Yee S. P., Pawson T. Novel protein-tyrosine kinase cDNAs related to fps/fes and eph cloned using anti-phosphotyrosine antibody. Oncogene. 1988 Dec;3(6):621–627. [PubMed] [Google Scholar]
  14. Maness P. F., Aubry M., Shores C. G., Frame L., Pfenninger K. H. c-src gene product in developing rat brain is enriched in nerve growth cone membranes. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5001–5005. doi: 10.1073/pnas.85.14.5001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Marth J. D., Lewis D. B., Wilson C. B., Gearn M. E., Krebs E. G., Perlmutter R. M. Regulation of pp56lck during T-cell activation: functional implications for the src-like protein tyrosine kinases. EMBO J. 1987 Sep;6(9):2727–2734. doi: 10.1002/j.1460-2075.1987.tb02566.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Martinez R., Mathey-Prevot B., Bernards A., Baltimore D. Neuronal pp60c-src contains a six-amino acid insertion relative to its non-neuronal counterpart. Science. 1987 Jul 24;237(4813):411–415. doi: 10.1126/science.2440106. [DOI] [PubMed] [Google Scholar]
  17. Pawson T., Guyden J., Kung T. H., Radke K., Gilmore T., Martin G. S. A strain of Fujinami sarcoma virus which is temperature-sensitive in protein phosphorylation and cellular transformation. Cell. 1980 Dec;22(3):767–775. doi: 10.1016/0092-8674(80)90553-x. [DOI] [PubMed] [Google Scholar]
  18. Quaife C. J., Pinkert C. A., Ornitz D. M., Palmiter R. D., Brinster R. L. Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice. Cell. 1987 Mar 27;48(6):1023–1034. doi: 10.1016/0092-8674(87)90710-0. [DOI] [PubMed] [Google Scholar]
  19. Quintrell N., Lebo R., Varmus H., Bishop J. M., Pettenati M. J., Le Beau M. M., Diaz M. O., Rowley J. D. Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. Mol Cell Biol. 1987 Jun;7(6):2267–2275. doi: 10.1128/mcb.7.6.2267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rigby P. W., Dieckmann M., Rhodes C., Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977 Jun 15;113(1):237–251. doi: 10.1016/0022-2836(77)90052-3. [DOI] [PubMed] [Google Scholar]
  21. Russo A. F., Crenshaw E. B., 3rd, Lira S. A., Simmons D. M., Swanson L. W., Rosenfeld M. G. Neuronal expression of chimeric genes in transgenic mice. Neuron. 1988 Jun;1(4):311–320. doi: 10.1016/0896-6273(88)90079-7. [DOI] [PubMed] [Google Scholar]
  22. Ryan T. M., Behringer R. R., Martin N. C., Townes T. M., Palmiter R. D., Brinster R. L. A single erythroid-specific DNase I super-hypersensitive site activates high levels of human beta-globin gene expression in transgenic mice. Genes Dev. 1989 Mar;3(3):314–323. doi: 10.1101/gad.3.3.314. [DOI] [PubMed] [Google Scholar]
  23. Rüther U., Garber C., Komitowski D., Müller R., Wagner E. F. Deregulated c-fos expression interferes with normal bone development in transgenic mice. 1987 Jan 29-Feb 4Nature. 325(6103):412–416. doi: 10.1038/325412a0. [DOI] [PubMed] [Google Scholar]
  24. Sadowski I., Stone J. C., Pawson T. A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps. Mol Cell Biol. 1986 Dec;6(12):4396–4408. doi: 10.1128/mcb.6.12.4396. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shibuya M., Hanafusa H. Nucleotide sequence of Fujinami sarcoma virus: evolutionary relationship of its transforming gene with transforming genes of other sarcoma viruses. Cell. 1982 Oct;30(3):787–795. doi: 10.1016/0092-8674(82)90283-5. [DOI] [PubMed] [Google Scholar]
  26. Sinn E., Muller W., Pattengale P., Tepler I., Wallace R., Leder P. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 1987 May 22;49(4):465–475. doi: 10.1016/0092-8674(87)90449-1. [DOI] [PubMed] [Google Scholar]
  27. Soriano P., Cone R. D., Mulligan R. C., Jaenisch R. Tissue-specific and ectopic expression of genes introduced into transgenic mice by retroviruses. Science. 1986 Dec 12;234(4782):1409–1413. doi: 10.1126/science.3024318. [DOI] [PubMed] [Google Scholar]
  28. Stewart T. A., Pattengale P. K., Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell. 1984 Oct;38(3):627–637. doi: 10.1016/0092-8674(84)90257-5. [DOI] [PubMed] [Google Scholar]
  29. Trudel M., Costantini F. A 3' enhancer contributes to the stage-specific expression of the human beta-globin gene. Genes Dev. 1987 Nov;1(9):954–961. doi: 10.1101/gad.1.9.954. [DOI] [PubMed] [Google Scholar]
  30. Trudel M., Magram J., Bruckner L., Costantini F. Upstream G gamma-globin and downstream beta-globin sequences required for stage-specific expression in transgenic mice. Mol Cell Biol. 1987 Nov;7(11):4024–4029. doi: 10.1128/mcb.7.11.4024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Weinmaster G., Zoller M. J., Smith M., Hinze E., Pawson T. Mutagenesis of Fujinami sarcoma virus: evidence that tyrosine phosphorylation of P130gag-fps modulates its biological activity. Cell. 1984 Jun;37(2):559–568. doi: 10.1016/0092-8674(84)90386-6. [DOI] [PubMed] [Google Scholar]
  32. Williams R. L., Courtneidge S. A., Wagner E. F. Embryonic lethalities and endothelial tumors in chimeric mice expressing polyoma virus middle T oncogene. Cell. 1988 Jan 15;52(1):121–131. doi: 10.1016/0092-8674(88)90536-3. [DOI] [PubMed] [Google Scholar]
  33. Yarden Y., Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443–478. doi: 10.1146/annurev.bi.57.070188.002303. [DOI] [PubMed] [Google Scholar]

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