Skip to main content
NCBI home page
Cellular and Molecular Neurobiology logoLink to Cellular and Molecular Neurobiology
. 2004 Aug;24(4):517–533. doi: 10.1023/B:CEMN.0000023627.79947.22

Processing, Distribution, and Function of VGF, a Neuronal and Endocrine Peptide Precursor

Andrea Levi 1, Gian-Luca Ferri 2, Elizabeth Watson 3, Roberta Possenti 4, Stephen R J Salton 3
PMCID: PMC11529936  PMID: 15233376

Abstract

1. The vgf gene encodes a neuropeptide precursor with a restricted pattern of expression that is limited to a subset of neurons in the central and peripheral nervous systems and to specific populations of endocrine cells in the adenohypophysis, adrenal medulla, gastrointestinal tract, and pancreas. In responsive neurons, vgf transcription is upregulated by neurotrophins, the basis for the original identification of VGF as nerve growth factor- (NGF) inducible in PC12 cells (A. Levi, J. D. Eldridge, and B. M. Paterson, Science 229:393–395, 1985).

2. In this review, we shall summarize data concerning the transcriptional regulation of vgf in vitro, the structural organization of the vgf promoter as well as the transcription factors which regulate its activity.

3. On the basis of in situ hybridization and immunohistochemical studies, the in vivo tissue-specific expression of VGF during differentiation and in the adult will be summarized.

4. Parallel biochemical data will be reviewed, addressing the proteolytical processing of the pro-VGF precursor within the secretory compartment of neuroendocrine cells.

5. Finally, analysis of the phenotype of VGF knockout mice will be discussed, implying a nonredundant role of VGF products in the regulation of energy storage and expenditure.

Keywords: VGF, neurotrophin, PC12, endocrine, feeding, metabolism, NGF, BDNF

REFERENCES

  1. Ahima, R. S., Saper, C. B., Flier, J. S., and Elmquist, J. K. (2000). Leptin regulation of neuroendocrine systems. Front. Neuroendocrinol.21:263–307. [DOI] [PubMed] [Google Scholar]
  2. Altshuler, D., and Hirschhorn, J. N. (1999). Upsetting the balance: VGF and the regulation of body weight. Neuron23:415–417. [DOI] [PubMed] [Google Scholar]
  3. Barsh, G. S., Farooqi, I. S., and O'Rahilly, S. (2000). Genetics of body-weight regulation. Nature404:644–651. [DOI] [PubMed] [Google Scholar]
  4. Baybis, M., and Salton, S. R. (1992). Nerve growth factor rapidly regulates VGF gene transcription through cycloheximide sensitive and insensitive pathways. FEBS Lett.308:202–206. [DOI] [PubMed] [Google Scholar]
  5. Benson, D. L., and Salton, S. R. (1996). Expression and polarization of VGF in developing hippocampal neurons. Brain Res. Dev. Brain Res.96:219–228. [DOI] [PubMed] [Google Scholar]
  6. Bonni, A., Ginty, D. D., Dudek, H., and Greenberg, M. E. (1995). Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals. Mol. Cell. Neurosci.6:168–183. [DOI] [PubMed] [Google Scholar]
  7. Canu, N., Possenti, R., Ricco, A. S., Rocchi, M., and Levi, A. (1997a). Cloning, structural organization analysis, and chromosomal assignment of the human gene for the neurosecretory protein VGF. Genomics45:443–446. [DOI] [PubMed] [Google Scholar]
  8. Canu, N., Possenti, R., Rinaldi, A. M., Trani, E., and Levi, A. (1997b). Molecular cloning and characterization of the human VGF promoter region. J. Neurochem.68:1390–1399. [DOI] [PubMed] [Google Scholar]
  9. Cho, K. O., Skarnes, W. C., Minsk, B., Palmieri, S., Jackson-Grusby, L., and Wagner, J. A. (1989). Nerve growth factor regulates gene expression by several distinct mechanisms. Mol. Cell. Biol.9:135–143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. D'Arcangelo, G., Habas, R., Wang, S., Halegoua, S., and Salton, S. R. (1996). Activation of codependent transcription factors is required for transcriptional induction of the vgf gene by nerve growth factor and Ras. Mol. Cell. Biol.16:4621–4631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Davis, B. M., Albers, K. M., Seroogy, K. B., and Katz, D. M. (1994). Overexpression of nerve growth factor in transgenic mice induces novel sympathetic projections to primary sensory neurons. J. Comp. Neurol.349:464–474. [DOI] [PubMed] [Google Scholar]
  12. Eagleson, K. L., Fairfull, L. D., Salton, S. R., and Levitt, P. (2001). Regional differences in neurotrophin availability regulate selective expression of VGF in the developing limbic cortex. J. Neurosci.21:9315–9324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ferri, G. L., Levi, A., and Possenti, R. (1992). A novel neuroendocrine gene product: Selective VGF8a gene expression and immuno-localisation of the VGF protein in endocrine and neuronal populations. Brain Res. Mol. Brain Res.13:139–143. [DOI] [PubMed] [Google Scholar]
  14. Ferri, G. L., Albers, K. M., and Possenti, R. (1998). Changes in the neurotrophin-inducible protein “VGF” in mice hyperexpressing NGF. Soc. Neurosci. Abst.24:630. [Google Scholar]
  15. Ferri, G. L., Gaudio, R. M., Cossu, M., Rinaldi, A. M., Polak, J. M., Berger, P., and Possenti, R. (1995). The “VGF” protein in rat adenohypophysis: Sex differences and changes during the estrous cycle and after gonadectomy. Endocrinology136:2244–2251. [DOI] [PubMed] [Google Scholar]
  16. Greene, L. A., and Tischler, A. S. (1976). Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. U.S.A.73:2424–2428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hahm, S., Fekete, C., Mizuno, T. M., Windsor, J., Yan, H., Boozer, C. N., Lee, C., Elmquist, J. K., Lechan, R. M., Mobbs, C. V., and Salton, S. R. (2002). VGF is required for obesity induced by diet, gold thioglucose treatment and agouti, and is differentially regulated in POMC-and NPY-containing arcuate neurons in response to fasting. J. Neurosci.22:6929–6938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hahm, S., Mizuno, T. M., Wu, T. J., Wisor, J. P., Priest, C. A., Kozak, C. A., Boozer, C. N., Peng, B., McEvoy, R. C., Good, P., Kelley, K. A., Takahashi, J. S., Pintar, J. E., Roberts, J. L., Mobbs, C. V., and Salton, S. R. (1999). Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance. Neuron23:537–548. [DOI] [PubMed] [Google Scholar]
  19. Harper, M. E., and Himms-Hagen, J. (2001). Mitochondrial efficiency: Lessons learned from transgenic mice. Biochim. Biophys. Acta1504:159–172. [DOI] [PubMed] [Google Scholar]
  20. Hawley, R. J., Scheibe, R. J., and Wagner, J. A. (1992). NGF induces the expression of the VGF gene through a cAMP response element. J. Neurosci.12:2573–2581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hevroni, D., Rattner, A., Bundman, M., Lederfein, D., Gabarah, A., Mangelus, M., Silverman, M. A., Kedar, H., Naor, C., Kornuc, M., Hanoch, T., Seger, R., Theill, L. E., Nedivi, E., Richter-Levin, G., and Citri, Y. (1998). Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms. J. Mol. Neurosci.10:75–98. [DOI] [PubMed] [Google Scholar]
  22. Kanemasa, K., Okamura, H., Kodama, T., and Ibata, Y. (1995a). Induction of VGF mRNA in neurons of the rat nucleus tractus solitarius and the dorsal motor nucleus of vagus in duodenal ulceration by cysteamine. Brain Res. Mol. Brain Res.32:55–62. [DOI] [PubMed] [Google Scholar]
  23. Kanemasa, K., Okamura, H., Kodama, T., Kashima, K., and Ibata, Y. (1995b). Time course of the induction of VGF mRNA in the dorsal vagal complex in rats with cysteamine-induced peptic ulcers. Brain Res. Mol. Brain Res.34:309–314. [DOI] [PubMed] [Google Scholar]
  24. Kaplan, D. R., and Miller, F. D. (2000). Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol.10:381–391. [DOI] [PubMed] [Google Scholar]
  25. Laslop, A., Mahata, S. K., Wolkersdorfer, M., Mahata, M., Srivastava, M., Seidah, N. G., Fischer-Colbrie, R., and Winkler, H. (1994). Large dense-core vesicles in rat adrenal after reserpine: Levels of mRNAs of soluble and membrane-bound constituents in chromaffin and ganglion cells indicate a biosynthesis of vesicles with higher secretory quanta. J. Neurochem.62:2448–2456. [DOI] [PubMed] [Google Scholar]
  26. Levi, A., Eldridge, J. D., and Paterson, B. M. (1985). Molecular cloning of a gene sequence regulated by nerve growth factor. Science229:393–395. [DOI] [PubMed] [Google Scholar]
  27. Lewin, G. R., and Barde, Y.-A. (1996). Physiology of the Neurotrophins. Ann. Rev. Neurosci.19:289–317. [DOI] [PubMed] [Google Scholar]
  28. Li, L., Suzuki, T., Mori, N., and Greengard, P. (1993). Identification of a functional silencer element involved in neuron-specific expression of the synapsin I gene. Proc. Natl. Acad. Sci. U.S.A.90:1460–1464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Liu, J. W., Andrews, P. C., Mershon, J. L., Yan, C., Allen, D. L., and Ben-Jonathan N. (1994). Peptide V: A VGF-derived neuropeptide purified from bovine posterior pituitary. Endocrinology135:2742–2748. [DOI] [PubMed] [Google Scholar]
  30. Lombardo, A., Rabacchi, S. A., Cremisi, F., Pizzorusso, T., Cenni, M. C., Possenti R., Barsacchi G., and Maffei L. (1995). A developmentally regulated nerve growth factor-induced gene, VGF, is expressed in geniculocortical afferents during synaptogenesis. Neuroscience65:997–1008. [DOI] [PubMed] [Google Scholar]
  31. Luc, P. V., and Wagner, J. A. (1997). Regulation of the neural-specific gene VGF in PC12 cells. Identification of transcription factors interacting with NGF-responsive elements. J. Mol. Neurosci.8:223–241. [DOI] [PubMed] [Google Scholar]
  32. Mahata, M., Hortnagl, H., Mahata, S. K., Fischer-Colbrie, R., and Winkler, H. (1993a). Messenger RNA levels of chromogranin B, secretogranin II, and VGF in rat brain after AF64A-induced septohippocampal cholinergic lesions. J. Neurochem.61:1648–1656. [DOI] [PubMed] [Google Scholar]
  33. Mahata, S. K., Mahata, M., Fischer-Colbrie, R., and Winkler, H. (1993b). In situ hybridization: mRNA levels of secretogranin II, VGF and peptidylglycine alpha-amidating monooxygenase in brain of salt-loaded rats. Histochemistry99:287–293. [DOI] [PubMed] [Google Scholar]
  34. Mahata, S. K., Mahata, M., Hortnag, H., Fischer-Colbrie, R., Steiner, H. J., Dietze, O., and Winkler, H. (1993c). Concomitant changes of messenger ribonucleic acid levels of secretogranin II, VGF, vasopressin and oxytocin in the paraventricular nucleus of rats after adrenalectomy and during lactation. J. Neuroendocrinol.5:323–330. [DOI] [PubMed] [Google Scholar]
  35. Mandolesi, G., Gargano, S., Pennuto, M., Illi, B., Molfetta, R., Soucek, L., Mosca, L., Levi, A., Jucker, R., and Nasi, S. (2002). NGF-dependent and tissue-specific transcription of vgf is regulated by a CREB-p300 and bHLH factor interaction. FEBS Lett.510:50–56. [DOI] [PubMed] [Google Scholar]
  36. Miller, F. D., and Kaplan, D. R. (2002). Neurobiology. TRK makes the retrograde. Science295:1471–1473. [DOI] [PubMed] [Google Scholar]
  37. Patapoutian, A., and Reichardt, L. F. (2001). Trk receptors: Mediators of neurotrophin action. Curr. Opin. Neurobiol.11:272–280. [DOI] [PubMed] [Google Scholar]
  38. Piccioli, P., Di Luzio, A., Amann, R., Schuligoi, R., Surani, M. A., Donnerer, J., and Cattaneo, A. (1995). Neuroantibodies: Ectopic expression of a recombinant anti-substance P antibody in the central nervous system of transgenic mice. Neuron15:373–384. [DOI] [PubMed] [Google Scholar]
  39. Possenti, R., Di Rocco, G., Nasi, S., and Levi, A. (1992). Regulatory elements in the promoter region of vgf, a nerve growth factor-inducible gene. Proc. Natl. Acad. Sci. U.S.A.89:3815–3819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Possenti, R., Eldridge, J. D., Paterson, B. M., Grasso, A., and Levi, A. (1989). A protein induced by NGF in PC12 cells is stored in secretory vesicles and released through the regulated pathway. EMBO J.8:2217–2223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Possenti, R., Rinaldi, A. M., Ferri, G. L., Borboni, P., Trani, E., and Levi, A. (1999). Expression, processing, and secretion of the neuroendocrine VGF peptides by INS-1 cells. Endocrinology140:3727–3735. [DOI] [PubMed] [Google Scholar]
  42. Puigserver, P., Adelmant, G., Wu, Z., Fan, M., Xu, J., O'Malley, B., and Spiegelman, B. M. (1999). Activation of PPARgamma coactivator-1 through transcription factor docking. Science286:1368–1371. [DOI] [PubMed] [Google Scholar]
  43. Salton, S. R. (1991). Nucleotide sequence and regulatory studies of VGF, a nervous system-specific mRNA that is rapidly and relatively selectively induced by nerve growth factor. J. Neurochem.57:991–996. [DOI] [PubMed] [Google Scholar]
  44. Salton, S. R., Fischberg, D. J., and Dong, K. W. (1991). Structure of the gene encoding VGF, a nervous system-specific mRNA that is rapidly and selectively induced by nerve growth factor in PC12 cells. Mol. Cell. Biol.11:2335–2349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Salton, S. R., Ferri, G. L., Hahm, S., Snyder, S. E., Wilson, A. J., Possenti, R., and Levi, A. (2000). VGF: A novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance. Front. Neuroendocrinol.21:199–219. [DOI] [PubMed] [Google Scholar]
  46. Schwartz, M. W., Woods, S. C., Porte, D., Jr., Seeley, R. J., and Baskin, D. G. (2000). Central nervous system control of food intake. Nature404:661–671. [DOI] [PubMed] [Google Scholar]
  47. Seidah, N. G., and Chretien, M. (1999). Proprotein and prohormone convertases: A family of subtilases generating diverse bioactive polypeptides. Brain Res.848:45–62. [DOI] [PubMed] [Google Scholar]
  48. Snyder, S. E., and Salton, S. R. (1998). Expression of VGF mRNA in the adult rat central nervous system. J. Comp. Neurol.394:91–105. [PubMed] [Google Scholar]
  49. Snyder, S. E., Pintar, J. E., and Salton, S. R. (1998a). Developmental expression of VGF mRNA in the prenatal and postnatal rat. J. Comp. Neurol.394:64–90. [PubMed] [Google Scholar]
  50. Snyder, S. E., Cheng, H. W., Murray, K. D., Isackson, P. J., McNeill, T. H., and Salton, S. R. (1998b). The messenger RNA encoding VGF, a neuronal peptide precursor, is rapidly regulated in the rat central nervous system by neuronal activity, seizure and lesion. Neuroscience82:7–19. [DOI] [PubMed] [Google Scholar]
  51. Stark, M., Danielsson, O., Griffiths, W. J., Jornvall, H., and Johansson, J. (2001). Peptide repertoire of human cerebrospinal fluid: Novel proteolytic fragments of neuroendocrine proteins. J. Chromatogr. B Biomed. Sci. Appl.754:357–367. [DOI] [PubMed] [Google Scholar]
  52. Steiner, D. F. (1998). The proprotein convertases.Curr. Opin. Chem. Biol.2:31–39. [DOI] [PubMed] [Google Scholar]
  53. Trani, E., Ciotti, T., Rinaldi, A. M., Canu, N., Ferri, G. L., Levi, A., and Possenti, R. (1995). Tissue-specific processing of the neuroendocrine protein VGF. J. Neurochem.65:2441–2449. [DOI] [PubMed] [Google Scholar]
  54. Tran, i E., Giorgi, A., Canu, N., Amadoro, G., Rinaldi, A. M., Halban, P. A., Ferri, G. L., Possenti, R., Schinina, M. E., and Levi, A. (2002). Isolation and characterization of VGF peptides in rat brain. Role of PC1/3 and PC2 in the maturation of VGF precursor. J. Neurochem.81:565–574. [DOI] [PubMed] [Google Scholar]
  55. Tschop, M., Smiley, D. L., and Heiman, M. L. (2000). Ghrelin induces adiposity in rodents. Nature407:908–913. [DOI] [PubMed] [Google Scholar]
  56. van den Pol, A. N., Decavel, C., Levi, A., and Paterson, B. (1989). Hypothalamic expression of a novel gene product, VGF: Immunocytochemical analysis. J. Neurosci.9:4122–4137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. van den Pol, A. N., Bina, K., Decavel, C., and Ghosh, P. (1994). VGF expression in the brain. J. Comp. Neurol.347:455–469. [DOI] [PubMed] [Google Scholar]
  58. Vaudry, D., Stork, P. J., Lazarovici, P., and Eiden, L. E. (2002). Signaling pathways for PC12 cell differentiation: Making the right connections. Science296:1648–1649. [DOI] [PubMed] [Google Scholar]
  59. Wren, A. M., Small, C. J., Abbott, C. R., Jethwa, P. H., Kennedy, A. R., Murphy, K. G., Stanley, S. A., Zollner, A. N., Ghatei, M. A., and Bloom, S. R. (2002). Hypothalamic actions of neuromedin U. Endocrinology143:4227–4234. [DOI] [PubMed] [Google Scholar]
  60. Wren, A. M., Small, C. J., Ward, H. L., Murphy, K. G., Dakin, C. L., Taheri, S., Kennedy, A. R., Roberts, G. H., Morgan, D. G., Ghatei, M. A., and Bloom, S. R. (2000). The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology141:4325–4328. [DOI] [PubMed] [Google Scholar]
  61. Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., and Spiegelman, B. M. (1999). Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell98:115–124. [DOI] [PubMed] [Google Scholar]

Articles from Cellular and Molecular Neurobiology are provided here courtesy of Springer

RESOURCES