Abstract
Fibroblast growth factors (FGF) are known to have key roles in embryonic growth and morphogenesis, but their presence and contributions to fetal development are unclear. In particular, little information exists as to the relevance of FGF and their specific receptors to human fetal development. We studied the anatomical distribution of messenger RNA encoding FGF-2 and one of its high affinity receptors, FGFR1, using in situ hybridization in a variety of human fetal tissues in early second trimester. Corresponding protein distributions were determined by immunohistochemistry. Both FGF-2 and FGFR1 mRNA and proteins were found to be present in every organ and tissue examined, but with defined cellular localizations. In skeletal muscle, both FGF-2 and FGFR1 mRNA and peptides were present in differentiated fibers, and both co-localized to proliferating chondrocytes of the epiphyseal growth plate. FGF-2 and FGFR1 mRNA and peptides were also present within cardiac or gastrointestinal smooth muscle. Within the gastrointestinal tract FGF-2 mRNA and peptide were located in the submucosal tissue, whereas FGFR1 was expressed within the overlying mucosa. Similarly, in skin, FGF-2 was expressed within the dermis whereas FGFR1 mRNA and peptide were most apparent in the stratum germinativum of the epidermis. In kidney and lung, FGFR1 mRNA was located in the tubular and alveolar epithelia respectively, whereas FGF-2 was expressed in both epithelial and mesenchymal cell populations. Both growth factor and receptor were widespread in both neuroblasts and glioblasts in the cerebral cortex of the brain. Immunoreactivity for FGF-2 and FGFR1 was seen in all vascular endothelial cells of major vessels and capillaries. Within the skin, kidney, lung, and intestine FGF-2 immunoreactivity was found in basement membranes underlying epithelia, and was associated with the extracellular matrix and plasma membranes of many cell types. The results show that FGF-2 and one of its receptors are widely expressed anatomically in the mid-trimester human fetus.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- FGF:
-
fibroblast growth factor
- FGFR:
-
fibroblast growth factor receptor
References
Baird A, Böhlen P 1990 Fibroblast growth factors. In: Sporn MB, Roberts AB (eds) Peptide Growth Factors and Their Receptors. Spring-Verlag, Berlin, pp 369–418.
Weise B, Janet T, Grothe C 1993 Localization of bFGF and FGF receptor in the developing nervous system of the embryonic and newborn rat. J Neurosci Res 34: 442–453.
Hebert JM, Basilico C, Goldfarb M, Haub O, Martin GR 1990 Isolation of cDNAs encoding four mouse FGF family members and characterization of their expression patterns during embryogenesis. Dev Biol 138: 454–463.
Johnson DE, Williams LT 1993 Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 40: 1–41.
Ron D, Reich R, Chedid M, Lengel C, Cohen OE, Chan AML, Neufeld G, Miki T, Tronick SR 1993 Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. J Biol Chem 268: 5388–5394.
Feldman B, Poueymirou W, Papaioannou VE, DeChiara TM, Goldfarb M 1995 Requirement for FGF-4 for postimplantation mouse development. Science 267: 246–249.
Niswander L, Jeffrey S, Martin GR, Tickle C 1994 A positive loop coordinates growth and patterning in the vertebrate limb. Nature 371: 609–612.
Amaya E, Musci TJ, Kirschner MW 1991 Expression of a dominant negative mutant of the FGF receptor disrupts mesoderm formation in Xenopus embryos. Cell 66: 257–270.
Kessler DS, Melton DA 1994 Vertebrate embryonic induction: mesodermal and neural patterning. Science 266: 596–604.
Mansour SL 1994 Targeted disruption of int-2 (fgf-3) causes developmental defects in the tail and inner ear. Mol Reprod Dev 39: 62–68.
Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L 1994 Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J 13: 3296–3301.
Gonzalez AM, Buscaglia M, Ong M, Baird A 1990 Distribution of basic fibroblast growth factor in 18-day rat fetus: Localization in the basement membranes of diverse tissues. J Cell Biol 110: 753–765.
Bashkin P, Doctrow S, Klagsbrun M, Suahn CM, Folkman J, Vlodavsky I 1989 Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules. Biochemistry 28: 1737–1743.
Ornitz DM, Yayon A, Flanagan JG, Svahn CM, Levi E, Leder P 1992 Heparin is required for cell-free binding of basic fibroblast growth factor to a soluble receptor and for mitogenesis in whole cells. Mol Cell Biol 12: 240–247.
Hsu SM, Raine L, Fanger H 1981 Use of avidin-biotin peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem 29: 577–580.
Gonzalez AM, Buscaglia M, Fox R, Isacchi A, Farris J, Ong M, Martineau D, Lappi DA, Baird A 1992 Basic fibroblast growth factor in Dupuytren's contracture. Am J Pathol 141: 661–671.
Yeh J, Osathanondh R 1993 Expression of messenger ribonucleic acid encoding for basic fibroblast growth factor (FGF) and alternatively spliced FGF receptor in human fetal ovary and uterus. J Clin Endocrinol Metab 77: 1367–1371.
Mesiano S, Mellon S, Gospodarowicz D, Di Blasio AM 1991 Basic fibroblast growth factor expression is regulated by corticotropin in the human fetal adrenal: A model for adrenal growth regulation. Proc Natl Acad Sci USA 88: 5428–5432.
Partanen J, Makela TP, Eerola E, Korhonen J, Hirvonen H, Claesson-Welsh L, Alitalo K 1991 FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. EMBO J 10: 1347–1354.
Partanen J, Vainikka S, Korhonen J, Armstrong E, Alitalo K 1992 Diverse receptors for fibroblast growth factors. Prog Growth Factor Res 4: 69–83.
Mignatti P, Morimoto T, Rifkin DB 1992 Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulum-Golgi complex. J Cell Physiol 151: 81–93.
Florkiewicz RZ, Majack RA, Buechler RD, Florkiewicz E 1995 Quantitative export of FGF-2 occurs through an alternative energy-dependent, non-ER/Golgi pathway. J Cell Physiol 162: 388–395.
Roghani M, Moscatelli D 1992 Basic fibroblast growth factor is internalized through both receptor-mediated and heparan sulfate-mediated mechanisms. J Biol Chem 267: 22156–22162.
Hill DJ, Tevaarwerk GJM, Arany E, Kilkenny D, Gregory M, Langford KS, Miell J 1995 Fibroblast growth factor-2 (FGF-2) is present in maternal and cord serum, and in the mother is associated with a binding protein immunologically related to the FGF receptor-1. J Clin Endocrinol Metab 80: 1822–1831.
Cattini PA, Nickol B, Bock M, Kardami E 1991 Immunolocalization of basic fibroblast growth factor (bFGF) in growing and growth inhibited placental cells: a possible role for bFGF in placental cell development. Placenta 12: 341–352.
Fernig DG, Gallagher JT 1994 Fibroblast growth factors and their receptors: An information network controlling tissue growth, morphogenesis and repair. Prog Growth Factor Res 5: 353–377.
Hill DJ, Logan A 1992 Cell cycle-dependent localization of immunoreactive basic fibroblast growth factor to cytoplasm and nucleus of isolated ovine fetal growth plate chondrocytes. Growth Factors 7: 215–231.
Baldin V, Roman A-M, Bosc-Bierne I, Amalric F, Bouche G 1990 Translocation of bFGF to the nucleus is G1 phase cell cycle specific in bovine aortic endothelial cells. EMBO J 9: 1511–1517.
Nakanishi Y, Kihara K, Mizuno K, Masamune Y, Yoshitake Y, Nishikawa K 1992 Direct effect of basic fibroblast growth factor on gene transcription in a cell-free system. Proc Natl Acad Sci USA 89: 5216–5220.
Bouche G, Baldin V, Belenguer P, Prats H, Amalric F 1994 Activation of rDNA transcription by FGF-2: key role of protein kinase CKII. Cell Mol Biol Res 40: 547–554.
Shiurba RA, Jing N, Sakakura T, Godsave SF 1991 Nuclear translocation of fibroblast growth factor during Xenopus mesoderm induction. Development 113: 487–493.
Pasumarthi KBS, Doble BW, Kardami E, Cattini PA 1994 Over-expression of CUG-or AUG-initiated forms of basic fibroblast growth factor in cardiac myocytes results in similar effects on mitosis and protein synthesis but distinct nuclear morphologies. J Mol Cell Cardiol 26: 1045–1060.
Prudovsky I, Savion N, Zhan X, Friesel R, Jianming X, Hou J, McKeeehan W, Maciag T 1994 Intact and functional fibroblast growth factor receptor-1 trafficks near the nucleus in response to FGF-1. J Biol Chem 269: 31720–31724.
Kilkenny DM, Hill DJ 1995 Cell cycle kinetics of an intracellular binding protein associated with the nuclear translocation of fibroblast growth factor-2. J Endocrinol 144 ( suppl 1): P245.
Vaidya TB, Rhodes SJ, Taparowsky EJ, Konieczny SF 1989 Fibroblast growth factor and transforming growth factor repress transcription of the myogenic regulatory gene MyoD1. Mol Cell Biol 9: 3576–3579.
Brunetti A, Goldfine ID 1990 Role of myogenin in myoblast differentiation and its regulation by fibroblast growth factor. J Biol Chem 265: 5960–5963.
Niswander L, Martin GR 1992 FGF-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development 114: 755–768.
Haub O, Goldfarb M 1991 Expression of fibroblast growth factor-5 gene in the mouse embryo. Development 112: 397–406.
Mima T, Ueno H, Fischman DA, Williams LT, Mikawa T 1995 Fibroblast growth factor receptor is required for in vivo cardiac myocyte proliferation at early embryonic stages of heart development. Proc Natl Acad Sci USA 92: 467–471.
Hill DJ, Logan A, Ong M, DeSousa D, Gonzalez AM 1992 Basic fibroblast growth factor is synthesized and released by isolated ovine fetal growth plate chondrocytes: Potential role as an autocrine mitogen. Growth Factors 6: 277–294.
Rousseau F, Bonaventure J, Legeal-Mallet L, Pelet A, Rozet J-M, Maroteaux P, Le Merrer M, Munnich A 1994 Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371: 252–254.
Han RNN, Liu J, Tanswell AK, Post M 1992 Expression of basic fibroblast growth factor and receptor: immunolocalization studies in developing rat fetal lung. Pediatr Res 31: 435–440.
Crickard J, Ill CR, Jaffe RB 1981 Control of proliferation of human fetal adrenal cells in vitro. J Clin Endocrinol Metab 53: 790–798.
Walicke PA, Baird A 1988 Neurotrophic effects of basic and acidic fibroblast growth factors are not mediated through glial cells. Brain Res 468: 71–79.
Brill G, Vaisman N, Neufeld G, Kalcheim C 1992 BHK-21-derived cell lines that produce basic fibroblast growth factor, but not parental BHK-21 cells, initiate neuronal differentiation of neural crest progenitors. Development 115: 1059–1069.
Mayer E, Dunnett SB, Pellitten R, Fawcett JW 1993 Basic fibroblast growth factor promotes the survival of embryonic ventral mesencephalic dopaminergic neurons 1. Effects in vitro. Neuroscience 56: 379–388.
Pechan PA, Chowdhury K, Gerdes W, Siefert W 1993 Glutamate induces the growth factors NGF, bFGF, the receptor FGFR1 and c-fos mRNA expression in rat astrocyte culture. Neurosci Lett 153: 111–114.
Mayer M, Bogler O, Noble M 1993 The inhibition of oligodendrocytic differentiation of O-2A progenitors caused by basic fibroblast growth factor is overidden by astrocytes. GLIA 8: 12–19.
Author information
Authors and Affiliations
Additional information
Supported in part by National Institutes of Health Grant DK 18811 (A.M.G., P.A.M., and A.B.), the Wellcome Trust (A.L.), and the Medical Research Council of Canada (D.J.H.). This manuscript is number 9464-CB from The Scripps Research Institute.
Rights and permissions
About this article
Cite this article
Gonzalez, A., Hill, D., Logan, A. et al. Distribution of Fibroblast Growth Factor (FGF)-2 and FGF Receptor-1 Messenger RNA Expression and Protein Presence in the Mid-Trimester Human Fetus. Pediatr Res 39, 375–385 (1996). https://doi.org/10.1203/00006450-199603000-00001
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/00006450-199603000-00001
This article is cited by
-
FGF/FGFR signaling in adrenocortical development and tumorigenesis: novel potential therapeutic targets in adrenocortical carcinoma
Endocrine (2022)
-
Association of circulating fibroblast growth factor-2 with progression of HIV-chronic kidney diseases in children
Pediatric Nephrology (2021)
-
Development of the Endocrine Pancreas
Reviews in Endocrine and Metabolic Disorders (2005)
