Logo of jcellbiolHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Cell Biol. Jul 1, 1995; 130(1): 137–148.
PMCID: PMC2120511

Peripheral expression and biological activities of GDNF, a new neurotrophic factor for avian and mammalian peripheral neurons

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic polypeptide, distantly related to transforming growth factor-beta (TGF- beta), originally isolated by virtue of its ability to induce dopamine uptake and cell survival in cultures of embryonic ventral midbrain dopaminergic neurons, and more recently shown to be a potent neurotrophic factor for motorneurons. The biological activities and distribution of this molecule outside the central nervous system are presently unknown. We report here on the mRNA expression, biological activities and initial receptor binding characterization of GDNF and a shorter spliced variant termed GDNF beta in different organs and peripheral neurons of the developing rat. Both GDNF mRNA forms were found to be most highly expressed in developing skin, whisker pad, kidney, stomach and testis. Lower expression was also detected in developing skeletal muscle, ovary, lung, and adrenal gland. Developing spinal cord, superior cervical ganglion (SCG) and dorsal root ganglion (DRG) also expressed low levels of GDNF mRNA. Two days after nerve transection, GDNF mRNA levels increased dramatically in the sciatic nerve. Overall, GDNF mRNA expression was significantly higher in peripheral organs than in neuronal tissues. Expression of either GDNF mRNA isoform in insect cells resulted in the production of indistinguishable mature GDNF polypeptides. Purified recombinant GDNF promoted neurite outgrowth and survival of embryonic chick sympathetic neurons. GDNF produced robust bundle-like, fasciculated outgrowth from chick sympathetic ganglion explants. Although GDNF displayed only low activity on survival of newborn rat SCG neurons, this protein was found to increase the expression of vasoactive intestinal peptide and preprotachykinin-A mRNAs in cultured SCG neurons. GDNF also promoted survival of about half of the neurons in embryonic chick nodose ganglion and a small subpopulation of embryonic sensory neurons in chick dorsal root and rat trigeminal ganglia. Embryonic chick sympathetic neurons expressed receptors for GDNF with Kd 1-5 x 10(-9) M, as measured by saturation and displacement binding assays. Our findings indicate GDNF is a new neurotrophic factor for developing peripheral neurons and suggest possible non-neuronal roles for GDNF in the developing reproductive system.

Full Text

The Full Text of this article is available as a PDF (2.4M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. 1982 Jul 15;298(5871):240–244. [PubMed]
  • Attisano L, Wrana JL, López-Casillas F, Massagué J. TGF-beta receptors and actions. Biochim Biophys Acta. 1994 May 26;1222(1):71–80. [PubMed]
  • Barde YA. Trophic factors and neuronal survival. Neuron. 1989 Jun;2(6):1525–1534. [PubMed]
  • Beck KD, Valverde J, Alexi T, Poulsen K, Moffat B, Vandlen RA, Rosenthal A, Hefti F. Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. Nature. 1995 Jan 26;373(6512):339–341. [PubMed]
  • Birren SJ, Lo L, Anderson DJ. Sympathetic neuroblasts undergo a developmental switch in trophic dependence. Development. 1993 Nov;119(3):597–610. [PubMed]
  • Cárcamo J, Weis FM, Ventura F, Wieser R, Wrana JL, Attisano L, Massagué J. Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin. Mol Cell Biol. 1994 Jun;14(6):3810–3821. [PMC free article] [PubMed]
  • Caroni P, Schneider C, Kiefer MC, Zapf J. Role of muscle insulin-like growth factors in nerve sprouting: suppression of terminal sprouting in paralyzed muscle by IGF-binding protein 4. J Cell Biol. 1994 May;125(4):893–902. [PMC free article] [PubMed]
  • Cheng B, Mattson MP. NGF and bFGF protect rat hippocampal and human cortical neurons against hypoglycemic damage by stabilizing calcium homeostasis. Neuron. 1991 Dec;7(6):1031–1041. [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Dechant G, Rodríguez-Tébar A, Kolbeck R, Barde YA. Specific high-affinity receptors for neurotrophin-3 on sympathetic neurons. J Neurosci. 1993 Jun;13(6):2610–2616. [PubMed]
  • Deschenes RJ, Lorenz LJ, Haun RS, Roos BA, Collier KJ, Dixon JE. Cloning and sequence analysis of a cDNA encoding rat preprocholecystokinin. Proc Natl Acad Sci U S A. 1984 Feb;81(3):726–730. [PMC free article] [PubMed]
  • DiCicco-Bloom E, Friedman WJ, Black IB. NT-3 stimulates sympathetic neuroblast proliferation by promoting precursor survival. Neuron. 1993 Dec;11(6):1101–1111. [PubMed]
  • Fann MJ, Patterson PH. Neuropoietic cytokines and activin A differentially regulate the phenotype of cultured sympathetic neurons. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):43–47. [PMC free article] [PubMed]
  • Funakoshi H, Frisén J, Barbany G, Timmusk T, Zachrisson O, Verge VM, Persson H. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol. 1993 Oct;123(2):455–465. [PMC free article] [PubMed]
  • Goodman RH, Aron DC, Roos BA. Rat pre-prosomatostatin. Structure and processing by microsomal membranes. J Biol Chem. 1983 May 10;258(9):5570–5573. [PubMed]
  • Henderson CE, Phillips HS, Pollock RA, Davies AM, Lemeulle C, Armanini M, Simmons L, Moffet B, Vandlen RA, Simpson LC [corrected to Simmons L], et al. GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science. 1994 Nov 11;266(5187):1062–1064. [PubMed]
  • Hughes RA, Sendtner M, Thoenen H. Members of several gene families influence survival of rat motoneurons in vitro and in vivo. J Neurosci Res. 1993 Dec 15;36(6):663–671. [PubMed]
  • Humpel C, Hoffer B, Strömberg I, Bektesh S, Collins F, Olson L. Neurons of the hippocampal formation express glial cell line-derived neurotrophic factor messenger RNA in response to kainate-induced excitation. Neuroscience. 1994 Apr;59(4):791–795. [PubMed]
  • Ibáez CF, Ernfors P, Timmusk T, Ip NY, Arenas E, Yancopoulos GD, Persson H. Neurotrophin-4 is a target-derived neurotrophic factor for neurons of the trigeminal ganglion. Development. 1993 Apr;117(4):1345–1353. [PubMed]
  • Ip NY, Boulton TG, Li Y, Verdi JM, Birren SJ, Anderson DJ, Yancopoulos GD. CNTF, FGF, and NGF collaborate to drive the terminal differentiation of MAH cells into postmitotic neurons. Neuron. 1994 Aug;13(2):443–455. [PubMed]
  • Kaplan DR, Martin-Zanca D, Parada LF. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature. 1991 Mar 14;350(6314):158–160. [PubMed]
  • Kawaguchi Y, Hoshimaru M, Nawa H, Nakanishi S. Sequence analysis of cloned cDNA for rat substance P precursor: existence of a third substance P precursor. Biochem Biophys Res Commun. 1986 Sep 30;139(3):1040–1046. [PubMed]
  • Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994 Jan;8(2):133–146. [PubMed]
  • Knusel B, Michel PP, Schwaber JS, Hefti F. Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. J Neurosci. 1990 Feb;10(2):558–570. [PubMed]
  • Levi-Montalcini R, Angeletti PU. Nerve growth factor. Physiol Rev. 1968 Jul;48(3):534–569. [PubMed]
  • Lewis SE, Rao MS, Symes AJ, Dauer WT, Fink JS, Landis SC, Hyman SE. Coordinate regulation of choline acetyltransferase, tyrosine hydroxylase, and neuropeptide mRNAs by ciliary neurotrophic factor and leukemia inhibitory factor in cultured sympathetic neurons. J Neurochem. 1994 Aug;63(2):429–438. [PubMed]
  • Lin LF, Mismer D, Lile JD, Armes LG, Butler ET, 3rd, Vannice JL, Collins F. Purification, cloning, and expression of ciliary neurotrophic factor (CNTF). Science. 1989 Nov 24;246(4933):1023–1025. [PubMed]
  • Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993 May 21;260(5111):1130–1132. [PubMed]
  • Lin LF, Zhang TJ, Collins F, Armes LG. Purification and initial characterization of rat B49 glial cell line-derived neurotrophic factor. J Neurochem. 1994 Aug;63(2):758–768. [PubMed]
  • Manthorpe M, Skaper SD, Barbin G, Varon S. Cholinergic neuronotrophic factors. Concurrent activities on certain nerve growth factor-responsive neurons. J Neurochem. 1982 Feb;38(2):415–421. [PubMed]
  • Mitsumoto H, Ikeda K, Klinkosz B, Cedarbaum JM, Wong V, Lindsay RM. Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science. 1994 Aug 19;265(5175):1107–1110. [PubMed]
  • Nagata K, Takei N, Nakajima K, Saito H, Kohsaka S. Microglial conditioned medium promotes survival and development of cultured mesencephalic neurons from embryonic rat brain. J Neurosci Res. 1993 Feb 15;34(3):357–363. [PubMed]
  • Near SL, Whalen LR, Miller JA, Ishii DN. Insulin-like growth factor II stimulates motor nerve regeneration. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11716–11720. [PMC free article] [PubMed]
  • Nishizawa M, Hayakawa Y, Yanaihara N, Okamoto H. Nucleotide sequence divergence and functional constraint in VIP precursor mRNA evolution between human and rat. FEBS Lett. 1985 Apr 8;183(1):55–59. [PubMed]
  • O'Malley EK, Sieber BA, Black IB, Dreyfus CF. Mesencephalic type I astrocytes mediate the survival of substantia nigra dopaminergic neurons in culture. Brain Res. 1992 Jun 5;582(1):65–70. [PubMed]
  • Oppenheim RW, Houenou LJ, Johnson JE, Lin LF, Li L, Lo AC, Newsome AL, Prevette DM, Wang S. Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature. 1995 Jan 26;373(6512):344–346. [PubMed]
  • Ozkaynak E, Schnegelsberg PN, Oppermann H. Murine osteogenic protein (OP-1): high levels of mRNA in kidney. Biochem Biophys Res Commun. 1991 Aug 30;179(1):116–123. [PubMed]
  • Ozkaynak E, Schnegelsberg PN, Jin DF, Clifford GM, Warren FD, Drier EA, Oppermann H. Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. J Biol Chem. 1992 Dec 15;267(35):25220–25227. [PubMed]
  • Persson H, Ibáez CF. Role and expression of neurotrophins and the trk family of tyrosine kinase receptors in neural growth and rescue after injury. Curr Opin Neurol Neurosurg. 1993 Feb;6(1):11–18. [PubMed]
  • Rao MS, Sun Y, Escary JL, Perreau J, Tresser S, Patterson PH, Zigmond RE, Brulet P, Landis SC. Leukemia inhibitory factor mediates an injury response but not a target-directed developmental transmitter switch in sympathetic neurons. Neuron. 1993 Dec;11(6):1175–1185. [PubMed]
  • Schaar DG, Sieber BA, Dreyfus CF, Black IB. Regional and cell-specific expression of GDNF in rat brain. Exp Neurol. 1993 Dec;124(2):368–371. [PubMed]
  • Smith J, Vyas S, Garcia-Arraras JE. Selective modulation of cholinergic properties in cultures of avian embryonic sympathetic ganglia. J Neurosci Res. 1993 Feb 15;34(3):346–356. [PubMed]
  • Springer JE, Mu X, Bergmann LW, Trojanowski JQ. Expression of GDNF mRNA in rat and human nervous tissue. Exp Neurol. 1994 Jun;127(2):167–170. [PubMed]
  • Strömberg I, Björklund L, Johansson M, Tomac A, Collins F, Olson L, Hoffer B, Humpel C. Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp Neurol. 1993 Dec;124(2):401–412. [PubMed]
  • Stöckli KA, Lottspeich F, Sendtner M, Masiakowski P, Carroll P, Götz R, Lindholm D, Thoenen H. Molecular cloning, expression and regional distribution of rat ciliary neurotrophic factor. Nature. 1989 Dec 21;342(6252):920–923. [PubMed]
  • Thoenen H. The changing scene of neurotrophic factors. Trends Neurosci. 1991 May;14(5):165–170. [PubMed]
  • Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, Olson L. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature. 1995 Jan 26;373(6512):335–339. [PubMed]
  • Unsicker K, Reichert-Preibsch H, Schmidt R, Pettmann B, Labourdette G, Sensenbrenner M. Astroglial and fibroblast growth factors have neurotrophic functions for cultured peripheral and central nervous system neurons. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5459–5463. [PMC free article] [PubMed]
  • Wright EM, Vogel KS, Davies AM. Neurotrophic factors promote the maturation of developing sensory neurons before they become dependent on these factors for survival. Neuron. 1992 Jul;9(1):139–150. [PubMed]
  • Yamamori T, Fukada K, Aebersold R, Korsching S, Fann MJ, Patterson PH. The cholinergic neuronal differentiation factor from heart cells is identical to leukemia inhibitory factor. Science. 1989 Dec 15;246(4936):1412–1416. [PubMed]
  • Yan Q, Matheson C, Lopez OT. In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. Nature. 1995 Jan 26;373(6512):341–344. [PubMed]
  • Yan Z, Winawer S, Friedman E. Two different signal transduction pathways can be activated by transforming growth factor beta 1 in epithelial cells. J Biol Chem. 1994 May 6;269(18):13231–13237. [PubMed]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...