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.
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REFERENCES
Ahima, R. S., Saper, C. B., Flier, J. S., and Elmquist, J. K. (2000). Leptin regulation of neuroendocrine systems. Front. Neuroendocrinol. 21:263–307.
Altshuler, D., and Hirschhorn, J. N. (1999). Upsetting the balance: VGF and the regulation of body weight. Neuron 23:415–417.
Barsh, G. S., Farooqi, I. S., and O'Rahilly, S. (2000). Genetics of body-weight regulation. Nature 404:644–651.
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.
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.
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.
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. Genomics 45:443–446.
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.
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.
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.
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.
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.
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.
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.
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. Endocrinology 136:2244–2251.
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.
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.
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. Neuron 23:537–548.
Harper, M. E., and Himms-Hagen, J. (2001). Mitochondrial efficiency: Lessons learned from transgenic mice. Biochim. Biophys. Acta 1504:159–172.
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.
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.
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.
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.
Kaplan, D. R., and Miller, F. D. (2000). Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10:381–391.
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.
Levi, A., Eldridge, J. D., and Paterson, B. M. (1985). Molecular cloning of a gene sequence regulated by nerve growth factor. Science 229:393–395.
Lewin, G. R., and Barde, Y.-A. (1996). Physiology of the Neurotrophins. Ann. Rev. Neurosci. 19:289–317.
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.
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. Endocrinology 135:2742–2748.
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. Neuroscience 65:997–1008.
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.
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.
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. Histochemistry 99:287–293.
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.
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.
Miller, F. D., and Kaplan, D. R. (2002). Neurobiology. TRK makes the retrograde. Science 295:1471–1473.
Patapoutian, A., and Reichardt, L. F. (2001). Trk receptors: Mediators of neurotrophin action. Curr. Opin. Neurobiol. 11:272–280.
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. Neuron 15:373–384.
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.
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.
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. Endocrinology 140:3727–3735.
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. Science 286:1368–1371.
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.
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.
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.
Schwartz, M. W., Woods, S. C., Porte, D., Jr., Seeley, R. J., and Baskin, D. G. (2000). Central nervous system control of food intake. Nature 404:661–671.
Seidah, N. G., and Chretien, M. (1999). Proprotein and prohormone convertases: A family of subtilases generating diverse bioactive polypeptides. Brain Res. 848:45–62.
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.
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.
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. Neuroscience 82:7–19.
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.
Steiner, D. F. (1998). The proprotein convertases.Curr. Opin. Chem. Biol. 2:31–39.
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.
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.
Tschop, M., Smiley, D. L., and Heiman, M. L. (2000). Ghrelin induces adiposity in rodents. Nature 407:908–913.
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.
van den Pol, A. N., Bina, K., Decavel, C., and Ghosh, P. (1994). VGF expression in the brain. J. Comp. Neurol. 347:455–469.
Vaudry, D., Stork, P. J., Lazarovici, P., and Eiden, L. E. (2002). Signaling pathways for PC12 cell differentiation: Making the right connections. Science 296:1648–1649.
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. Endocrinology 143:4227–4234.
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. Endocrinology 141:4325–4328.
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. Cell 98:115–124.
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Levi, A., Ferri, GL., Watson, E. et al. Processing, Distribution, and Function of VGF, a Neuronal and Endocrine Peptide Precursor. Cell Mol Neurobiol 24, 517–533 (2004). https://doi.org/10.1023/B:CEMN.0000023627.79947.22
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DOI: https://doi.org/10.1023/B:CEMN.0000023627.79947.22