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. 1995 Jan 17;92(2):467–471. doi: 10.1073/pnas.92.2.467

Fibroblast growth factor receptor is required for in vivo cardiac myocyte proliferation at early embryonic stages of heart development.

T Mima 1, H Ueno 1, D A Fischman 1, L T Williams 1, T Mikawa 1
PMCID: PMC42761  PMID: 7831312

Abstract

In birds and mammals, cardiac myocytes terminate mitotic activity in the neonatal period and regeneration of cardiac muscle does not occur after myocardial injury in adult hearts. Even embryonic myocytes, which actively proliferate in vivo, quickly lose mitotic activity when placed in cell culture. Several growth factors, including fibroblast growth factor (FGF), have been documented in embryonic hearts and some have been shown to influence myocyte terminal differentiation in culture. However, none of these growth factors have been shown to reactivate cell division in postmitotic myocytes nor have their in vivo functions been defined satisfactorily. To clarify the role of FGF signaling in heart growth, we prepared two retroviral vectors capable of suppressing (i) functions of FGF receptors (FGFRs) with a dominant-negative mutant of receptor type 1 (FGFR1) or (ii) the translation of endogenous FGFR1 by transcribing its antisense RNA. Both vectors inhibited myocyte proliferation and/or survival during the first week of chicken embryonic development but had much less effect after the second week. No apparent alteration of myocyte growth was observed after overexpression of full-length FGFR1. These results suggest that receptor-coupled FGF signaling regulates cardiac myocyte growth during tubular stages of cardiogenesis but that myocyte growth becomes FGF-independent after the second week of embryogenesis.

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Selected References

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

  1. Adam M. A., Ramesh N., Miller A. D., Osborne W. R. Internal initiation of translation in retroviral vectors carrying picornavirus 5' nontranslated regions. J Virol. 1991 Sep;65(9):4985–4990. doi: 10.1128/jvi.65.9.4985-4990.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Amaya E., Musci T. J., Kirschner M. W. Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos. Cell. 1991 Jul 26;66(2):257–270. doi: 10.1016/0092-8674(91)90616-7. [DOI] [PubMed] [Google Scholar]
  3. Bisaha J. G., Bader D. Identification and characterization of a ventricular-specific avian myosin heavy chain, VMHC1: expression in differentiating cardiac and skeletal muscle. Dev Biol. 1991 Nov;148(1):355–364. doi: 10.1016/0012-1606(91)90343-2. [DOI] [PubMed] [Google Scholar]
  4. Buchou T., Mester J. Fibroblast growth factor-dependent mitogenic signal transduction pathway in chemically transformed mouse fibroblasts is similar to but distinct from that initiated by phorbol esters. J Cell Physiol. 1990 Mar;142(3):559–565. doi: 10.1002/jcp.1041420315. [DOI] [PubMed] [Google Scholar]
  5. Clark W. A., Jr, Fischman D. A. Analysis of population cytokinetics of chick myocardial cells in tissue culture. Dev Biol. 1983 May;97(1):1–9. doi: 10.1016/0012-1606(83)90057-x. [DOI] [PubMed] [Google Scholar]
  6. Consigli S. A., Joseph-Silverstein J. Immunolocalization of basic fibroblast growth factor during chicken cardiac development. J Cell Physiol. 1991 Mar;146(3):379–385. doi: 10.1002/jcp.1041460307. [DOI] [PubMed] [Google Scholar]
  7. Cornell R. A., Kimelman D. Activin-mediated mesoderm induction requires FGF. Development. 1994 Feb;120(2):453–462. doi: 10.1242/dev.120.2.453. [DOI] [PubMed] [Google Scholar]
  8. Dougherty J. P., Temin H. M. Determination of the rate of base-pair substitution and insertion mutations in retrovirus replication. J Virol. 1988 Aug;62(8):2817–2822. doi: 10.1128/jvi.62.8.2817-2822.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Du J., Gouras P., Kjeldbye H., Kwun R., Lopez R. Monitoring photoreceptor transplants with nuclear and cytoplasmic markers. Exp Neurol. 1992 Jan;115(1):79–86. doi: 10.1016/0014-4886(92)90226-g. [DOI] [PubMed] [Google Scholar]
  10. Engelmann G. L., Dionne C. A., Jaye M. C. Acidic fibroblast growth factor and heart development. Role in myocyte proliferation and capillary angiogenesis. Circ Res. 1993 Jan;72(1):7–19. doi: 10.1161/01.res.72.1.7. [DOI] [PubMed] [Google Scholar]
  11. Ghattas I. R., Sanes J. R., Majors J. E. The encephalomyocarditis virus internal ribosome entry site allows efficient coexpression of two genes from a recombinant provirus in cultured cells and in embryos. Mol Cell Biol. 1991 Dec;11(12):5848–5859. doi: 10.1128/mcb.11.12.5848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gonzalez-Sanchez A., Bader D. In vitro analysis of cardiac progenitor cell differentiation. Dev Biol. 1990 May;139(1):197–209. doi: 10.1016/0012-1606(90)90288-t. [DOI] [PubMed] [Google Scholar]
  13. Han Y., Dennis J. E., Cohen-Gould L., Bader D. M., Fischman D. A. Expression of sarcomeric myosin in the presumptive myocardium of chicken embryos occurs within six hours of myocyte commitment. Dev Dyn. 1992 Mar;193(3):257–265. doi: 10.1002/aja.1001930306. [DOI] [PubMed] [Google Scholar]
  14. Horlick R. A., Stack S. L., Cooke G. M. Cloning, expression and tissue distribution of the gene encoding rat fibroblast growth factor receptor subtype 4. Gene. 1992 Oct 21;120(2):291–295. doi: 10.1016/0378-1119(92)90108-2. [DOI] [PubMed] [Google Scholar]
  15. Jeter J. R., Jr, Cameron I. L. Cell proliferation patterns during cytodifferentiation in embryonic chick tissues: liver, heart and erythrocytes. J Embryol Exp Morphol. 1971 Jun;25(3):405–422. [PubMed] [Google Scholar]
  16. Kamino K., Hirota A., Fujii S. Localization of pacemaking activity in early embryonic heart monitored using voltage-sensitive dye. Nature. 1981 Apr 16;290(5807):595–597. doi: 10.1038/290595a0. [DOI] [PubMed] [Google Scholar]
  17. Koo H. M., Brown A. M., Kaufman R. J., Prorock C. M., Ron Y., Dougherty J. P. A spleen necrosis virus-based retroviral vector which expresses two genes from a dicistronic mRNA. Virology. 1992 Feb;186(2):669–675. doi: 10.1016/0042-6822(92)90033-l. [DOI] [PubMed] [Google Scholar]
  18. LaBonne C., Whitman M. Mesoderm induction by activin requires FGF-mediated intracellular signals. Development. 1994 Feb;120(2):463–472. doi: 10.1242/dev.120.2.463. [DOI] [PubMed] [Google Scholar]
  19. Lee P. L., Johnson D. E., Cousens L. S., Fried V. A., Williams L. T. Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science. 1989 Jul 7;245(4913):57–60. doi: 10.1126/science.2544996. [DOI] [PubMed] [Google Scholar]
  20. Mikawa T., Borisov A., Brown A. M., Fischman D. A. Clonal analysis of cardiac morphogenesis in the chicken embryo using a replication-defective retrovirus: I. Formation of the ventricular myocardium. Dev Dyn. 1992 Jan;193(1):11–23. doi: 10.1002/aja.1001930104. [DOI] [PubMed] [Google Scholar]
  21. Mikawa T., Cohen-Gould L., Fischman D. A. Clonal analysis of cardiac morphogenesis in the chicken embryo using a replication-defective retrovirus. III: Polyclonal origin of adjacent ventricular myocytes. Dev Dyn. 1992 Oct;195(2):133–141. doi: 10.1002/aja.1001950208. [DOI] [PubMed] [Google Scholar]
  22. Mikawa T., Fischman D. A., Dougherty J. P., Brown A. M. In vivo analysis of a new lacZ retrovirus vector suitable for cell lineage marking in avian and other species. Exp Cell Res. 1991 Aug;195(2):516–523. doi: 10.1016/0014-4827(91)90404-i. [DOI] [PubMed] [Google Scholar]
  23. Mikawa T., Fischman D. A. Retroviral analysis of cardiac morphogenesis: discontinuous formation of coronary vessels. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9504–9508. doi: 10.1073/pnas.89.20.9504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Miyamoto M., Naruo K., Seko C., Matsumoto S., Kondo T., Kurokawa T. Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property. Mol Cell Biol. 1993 Jul;13(7):4251–4259. doi: 10.1128/mcb.13.7.4251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Muslin A. J., Williams L. T. Well-defined growth factors promote cardiac development in axolotl mesodermal explants. Development. 1991 Aug;112(4):1095–1101. doi: 10.1242/dev.112.4.1095. [DOI] [PubMed] [Google Scholar]
  26. Nabeshima Y., Fujii-Kuriyama Y., Muramatsu M., Ogata K. Alternative transcription and two modes of splicing results in two myosin light chains from one gene. Nature. 1984 Mar 22;308(5957):333–338. doi: 10.1038/308333a0. [DOI] [PubMed] [Google Scholar]
  27. Olwin B. B., Hauschka S. D. Fibroblast growth factor receptor levels decrease during chick embryogenesis. J Cell Biol. 1990 Feb;110(2):503–509. doi: 10.1083/jcb.110.2.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Parker T. G., Packer S. E., Schneider M. D. Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. J Clin Invest. 1990 Feb;85(2):507–514. doi: 10.1172/JCI114466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Parlow M. H., Bolender D. L., Kokan-Moore N. P., Lough J. Localization of bFGF-like proteins as punctate inclusions in the preseptation myocardium of the chicken embryo. Dev Biol. 1991 Jul;146(1):139–147. doi: 10.1016/0012-1606(91)90454-b. [DOI] [PubMed] [Google Scholar]
  30. Partanen J., Mäkelä T. P., Eerola E., Korhonen J., Hirvonen H., Claesson-Welsh L., Alitalo K. FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO J. 1991 Jun;10(6):1347–1354. doi: 10.1002/j.1460-2075.1991.tb07654.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pasquale E. B., Singer S. J. Identification of a developmentally regulated protein-tyrosine kinase by using anti-phosphotyrosine antibodies to screen a cDNA expression library. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5449–5453. doi: 10.1073/pnas.86.14.5449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Patstone G., Pasquale E. B., Maher P. A. Different members of the fibroblast growth factor receptor family are specific to distinct cell types in the developing chicken embryo. Dev Biol. 1993 Jan;155(1):107–123. doi: 10.1006/dbio.1993.1011. [DOI] [PubMed] [Google Scholar]
  33. Peters K. G., Werner S., Chen G., Williams L. T. Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development. 1992 Jan;114(1):233–243. doi: 10.1242/dev.114.1.233. [DOI] [PubMed] [Google Scholar]
  34. Spirito P., Fu Y. M., Yu Z. X., Epstein S. E., Casscells W. Immunohistochemical localization of basic and acidic fibroblast growth factors in the developing rat heart. Circulation. 1991 Jul;84(1):322–332. doi: 10.1161/01.cir.84.1.322. [DOI] [PubMed] [Google Scholar]
  35. Sugi Y., Sasse J., Lough J. Inhibition of precardiac mesoderm cell proliferation by antisense oligodeoxynucleotide complementary to fibroblast growth factor-2 (FGF-2). Dev Biol. 1993 May;157(1):28–37. doi: 10.1006/dbio.1993.1109. [DOI] [PubMed] [Google Scholar]
  36. Taira M., Yoshida T., Miyagawa K., Sakamoto H., Terada M., Sugimura T. cDNA sequence of human transforming gene hst and identification of the coding sequence required for transforming activity. Proc Natl Acad Sci U S A. 1987 May;84(9):2980–2984. doi: 10.1073/pnas.84.9.2980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ueno H., Gunn M., Dell K., Tseng A., Jr, Williams L. A truncated form of fibroblast growth factor receptor 1 inhibits signal transduction by multiple types of fibroblast growth factor receptor. J Biol Chem. 1992 Jan 25;267(3):1470–1476. [PubMed] [Google Scholar]
  38. Werner S., Weinberg W., Liao X., Peters K. G., Blessing M., Yuspa S. H., Weiner R. L., Williams L. T. Targeted expression of a dominant-negative FGF receptor mutant in the epidermis of transgenic mice reveals a role of FGF in keratinocyte organization and differentiation. EMBO J. 1993 Jul;12(7):2635–2643. doi: 10.1002/j.1460-2075.1993.tb05924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Whitman M., Melton D. A. Growth factors in early embryogenesis. Annu Rev Cell Biol. 1989;5:93–117. doi: 10.1146/annurev.cb.05.110189.000521. [DOI] [PubMed] [Google Scholar]

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