Abstract
Many studies have revealed the free radical nitric oxide (NO) to be an important modulator of vascular and neuronal physiology. It also plays a developmental role in regulating synapse formation and patterning. Recent studies suggest that NO may also mediate the switch from proliferation to differentiation during neurogenesis. Many mechanisms of this response are conserved between neuronal precursor cells and the cells of the vascular system, where NO can inhibit the proliferative response of endothelial and smooth-muscle cells to injury. In cultured neuroblastoma cells, NO synthase (NOS) expression is increased in the presence of various growth factors and mitogens. Subsequent production of NO leads to cessation of cell division and the acquisition of a differentiated phenotype. The inhibitory action of NO on neuroblast proliferation has also been demonstrated in vivo for vertebrate and invertebrate nervous systems, as well as in the adult brain. Potential downstream effectors of NO include the second messenger cyclic GMP, activation of the tumor-suppressor genes p53 and Rb, and the cyclin-dependent kinase inhibitor p21. These studies highlight a new role for NO in the nervous system, as a coordinator of proliferation and patterning during neural development and adult neurogenesis.
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Wessley O. and De Robertis E. M. (2002) Neural plate patterning by secreted signals. Neuron 33, 489–491.
Zernicka-Goetz M. (2002) Patterning of the embryo: the first spatial decisions in the life of a mouse. Development 129, 815–829.
Marti E. and Bovolenta P. (2002) Sonic hedgehog in CNS development: one signal, multiple outputs. Trends Neurosci. 25, 89–96.
McLean D. L. and Sillar K. T. (2002) Nitric oxide selectively tunes inhibitory synapses to modulate vertebrate locomotion. J. Neurosci. 22, 4175–4184.
Palmer R. M., Ferrige A. G., and Moncada S. (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327, 524–526.
Gelperin A., Kleinfeld D., Denk W., and Cooke I. R. (1996) Oscillations and gaseous oxides in invertebrate olfaction. J. Neurobiol. 30, 110–122.
Scholz N., de Vente J., Truman J. W., and Graubard K. (2001) Neural network partitioning by NO and cGMP. J. Neurosci. 21, 1610–1618.
Hawkins R. D., Son H., and Arancio O. (1998) Nitric oxide as a retrograde messenger during long-term potentiation in the hippocampus. Prog. Brain Res. 118, 155–172.
Daniel H., Levenes C., and Crepel F. (1998) Cellular mechanisms of LTD. Trends Neurosci. 9, 401–407.
Wu H. H., Williams C. V., and McLoon S. C. (1994) Involvement of nitric oxide in the elimination of a transient retinotectal projection in development. Science 265, 1593–1596.
Cramer K. S., Angelucci A., Hahm J. O., Bogdanov M. B., and Sur M. (1996) A role for nitric oxide in the development of the ferret retinogeniculate projection. J. Neurosci. 16, 7995–8004.
Gibbs S. M. and Truman J. W. (1998) Nitric oxide and cyclic GMP regulate retinal patterning in the optic lobe of Drosophila. Neuron 20, 83–93.
Ernst A. F., Wu H. H., El-Fakahany E. E., and McLoon S. C. (1999) NMDA-receptor-mediated refinement of a transient retinotectal projection requires nitric oxide. J. Neurosci. 19, 229–235.
Wu H. H., Cork R. J., Huang P. L., Shuman D. L., and Mize R. R. (2000) Refinement of the ipsilateral retinocollicular projection is disrupted in double endothelial and neuronal nitric oxide synthase gene knockout mice. Brain Res. Dev. Brain Res. 120, 105–111.
Leamy C. A., Ho-Pao C. L., Sur M. (2001) Disruption of retinogeniculate pattern formation by inhibition of soluble guanylate cyclase. J. Neurosci. 21, 3871–3880.
Gibbs S. M., Becker A., Hardy R. W., and Truman J. W. (2001) Soluble guanylate cyclase is required during development for visual system function in Drosophila. J. Neurosci. 21, 7705–7714.
Marletta M. A. (1989) Nitric oxide: biosynthesis and biological significance. Trends Biochem. Sci. 14, 488–492.
Bredt D. S., Hwang P. M., Glatt C. E., Lowenstein C., Reed R. R., and Snyder S. H. (1991) Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 351, 714–718.
Mayer B. (1994) Regulation of nitric oxide synthase and soluble guanylate cyclase. Cell. Biochem. Funct 12, 167–177.
Stuehr D. J. (1999) Mammalian nitric oxide synthases. Biochem. Biophys. Acta 11411, 217–230.
Crane B. R., Rosenfeld R. J., Arvai A. S., Ghosh D. K., Ghosh S., Tainer J. A., et al. (1999) N-terminal domain swapping and metal ion binding in nitric oxide synthase dimerization. EMBO J. 18, 6271–6281.
Hope B. T., Michael G. J., Knigge K. M., and Vincent S. R. (1991) Neuronal NADPH diaphorase is a nitric oxide synthase. Proc. Natl. Acad. Sci. USA 88, 2811–2814.
Bredt D. S., Glatt C. E., Hwang P. M., Fotuhi M., Dawson T. M., and Snyder S. H. (1991) Nitric oxide synthase protein and mRNA are discretely localized together in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 7, 615–624.
Geller D. A. and Billiar T. R. (1998) Molecular biology of nitric oxide synthases. Cancer Metastasis Rev. 17, 7–23.
Wang Y., Newton D. C., and Marsden P. A. (1999) Neuronal NOS: gene structure, mRNA diversity, and functional relevance. Crit. Rev. Neurobiol. 13, 21–43.
Regulski M. and Tully T. (1995) Molecular and biochemical characterization of dNOS- a Drosophila Ca2+-calmodulin-dependent nitric oxide synthase. Proc. Natl. Acad. Sci. USA 92, 9072–9076.
Peunova N., Scheinker V., Cline H., and Enikolopov G. (2001) Nitric oxide is an essential regulator of cell proliferation in Xenopus brain. J. Neurosci. 21, 8809–8818.
Holmqvist B., Ellingsen B., Alm P., Forsell J., Oyan A. M., Goksoyr A., et al. (2000) Identification and distribution of nitric oxide synthase in the brain of adult zebrafish. Neurosci. Lett. 292, 119–122.
Cox R. L., Mariano T., Heck D. E., Laskin J. D., and Stegeman J. J. (2001) Nitric oxide synthase sequences in the marine fish Stenotomus chrysops and the sea urchin Arbacia punctulata, and phylogenetic analysis of nitric oxide synthase calmodulin-binding domains. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 130, 479–491.
Forstermann U., Biossel J. P., and Kleinert H. (1998) Expressional control of the “constitutive” isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J. 12, 773–790.
Lancaster Jr. J. R. (1997) A tutorial on the diffusibility and reactivity of free nitric oxide. Nitric Oxide: Biol. Chem. 1, 18–30.
Schulz S., Chinkers M., and Garbers D. L. (1989) The guanylate cyclase/receptor family of proteins. FASEB J. 3, 2026–2035.
Arnold W. P., Mittal C. K., Katsuki S., and Murad F. (1977) Nitric oxide activates guanylate cyclase and increases guanosine 3′,5′-cyclic monophosphate levels in various tissue preparations. Proc. Natl. Acad. Sci. USA 74, 3202–3207.
Farber D. B., Brown D. M., and Lilley R. N. (1979) Cyclic nucleotide dependent protein kinase and the phosphorylation of endogenous proteins of retinal rod outer segments. Biochemistry 18, 370–378.
Paupardin-Tritsch D., Hammond C., Gerschenfeld H. M., Nairn A. C., and Greengard P. (1986) cGMP-dependent protein kinase enhances Ca2+ current and potentiates the serotonin-induced Ca2+ current increase in snail neurons. Nature 323, 812–814.
Hartzell H. C. and Fishmeister R. (1986) Opposite effects of cyclic GMP and cyclic AMP on Ca2+ current in single heart cells. Nature 323, 273–275.
Johnson E. C., Robinson P. R., and Lisman J. E. (1986) Cyclic GMP is involved in the excitation of invertebrate photoreceptors. Nature 324, 468–470.
Nawy S. and Jahr C. E. (1990) Suppression by glutamate of cGMP-activated conductance in retinal bipolar cells. Nature 346, 269–271.
Gudi T., Hong G. K.-P., Vaandrager A. B., Lohmann S. M., and Pilz R. B. (1999) Nitric oxide and cGMP regulate gene expression in neuronal and glial cells by activating type II cGMP-dependent protein kinase. FASEB J. 13, 2143–2152.
Dawson T. M. and Dawson V. L. (1995) Nitric oxide: actions and pathological roles. Neuroscientist 1, 7–18.
Garthwaite J. and Boulton C. L. (1995) Nitric oxide signaling in the central nervous system. Annu. Rev. Physiol. 57, 683–706.
Ishida A., Sasaguri T., Kosaka C., Nojima H., Ogata J. (1997) Induction of the cyclin-dependent kinase inhibitor p21(Sdi1/Cip1/Waf1) by nitric oxide-generating vasodilator in vascular smooth muscle cells. J. Biol. Chem. 272, 10,050–10,057.
Poluha W., Schonhoff C. M., Harrington K. S., Lachyankar M. B., Crosbie N. E., Bulesco D. A., et al. (1997) A novel, nerve-growth factor-activated pathway involving nitric oxide, p53, and p21WAF1 regulates neuronal differentiation of PC12 cells. J. Biol. Chem. 272, 24,002–24,007.
Tanner F. C., Meier P., Greutert H., Champion C., Nabel E. G., and Luscher T. F. (2000) Nitric oxide modulates expression of cell cycle regulatory proteins: a cytostatic strategy for inhibition of human vascular smooth muscle cell proliferation. Circulation 101, 1982–1989.
Nakaya N., Lowe S. W., Taya Y., Chenchik A., and Enikolopov G. (2000) Specific pattern of p53 phosphorylation during nitric oxide-induced cell cycle arrest. Oncogene 19, 6369–6375.
Meffert M. K., Premack B. A., and Schulman H. (1994) Nitric oxide stimulates calcium-independent synaptic vesicle release. Neuron 12, 1235–1244.
Meffert M. K., Calakos N. C., Scheller R. H., and Schulman H. (1996) Nitric oxide modulates synaptic vesicle docking/fusion reactions. Neuron 16, 1229–1236.
Sporns O. and Jenkinson S. (1997) Potassium ion- and nitric oxide-induced exocytosis from population of hippocampal synapses during synaptic maturation in vitro. Neuroscience 80, 1057–1073.
Jeremy J. Y., Rowe D., Emsley A. M., and Newby A. C. (1999) Nitric oxide and the proliferation of vascular smooth muscle cells. Cardiovasc. Res. 43, 580–594.
Yang W., Ando J., Korenaga R., Toyo-aka T., and Kamiya A. (1994) Exogenous nitric oxide inhibits proliferation of cultured endothelial cells. Biochem. Biophys. Res. Commun. 203, 1160–1167.
Sarkar R., Webb R. C., and Stanley J. C. (1995) Nitric oxide inhibition of endothelial cell mitogenesis and proliferation. Surgery 118, 274–279.
Garg U. C. and Hassid A. (1989) Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J. Clin. Investig. 83, 1774–1777.
Kariya K., Kawahara Y., Araki S., Fukuzaki H., and Takai Y. (1989) Antiproliferative action of cyclic GMP-elevating vasodilators in cultured rabbit aortic smooth muscle cells. Atherosclerosis 80, 143–147.
Assender J. W., Southgate K. M., Hallet M. B., and Newby A. C. (1992) Inhibition of proliferation, but not Ca2+ mobilization, by cyclic AMP and GMP in rabbit aortic smooth-muscle cells. Biochem. J. 288, 527–532.
Cartwright J. E., Johnstone A. P., and Whitley G. S. (2000) Endogenously produced nitric oxide inhibits endothelial cell growth as demonstrated using novel antisense cell lines. Br. J. Pharmacol. 13, 131–137.
Rudic R. D., Shesely E. G., Maeda N., Smithies O., Segal S. S., and Sessa W. C. (1998) Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J. Clin. Investig. 101, 731–736.
von der Leyen H. E., Gibbons G. H., and Morishita R. (1995) Gene therapy inhibiting neointimal hyperplasia in vivo: transfer of endothelial nitric oxide synthase gene. Proc. Natl. Acad. Sci. USA 92, 1137–1141.
Channon K. M., Blazing M. A., Shetty G. A., Potts K. E., and George S. E. (1996) Adenoviral gene transfer of nitric oxide synthase: high level expression in human vascular cells. Cardiovasc. Res. 32, 962–972.
Chiche J-D., Schlutsmeyer S. M., Bloch D. B., de la Monte S. M., Roberts J. D., Filippov G., et al. (1998) Adenovirus-mediated gene transfer of cGMP-dependent protein kinase increases the sensitivity of cultured vascular smooth muscle cells to the antiproliferative and proapoptotic effects of nitric oxide/cGMP. J. Biol. Chem. 273, 34,263–34,271.
Sinnaeve P., Chiche J-D., Nong Z., Varenne O., Van Pelt N., Gillijns H., et al. (2001) Soluble guanylate cyclase α1 and β1 gene transfer increases NO responsiveness and reduces neointima formation after balloon injury in rats via antiproliferative and antimigratory effects. Circ. Res. 88, 103–109.
Wingrove J. A. and O’Farrell P. H. (1999) Nitric oxide contributes to behavioral, cellular, and developmental responses to low oxygen in Drosophila. Cell 98, 105–114.
Kuzin B., Roberts I., Peunova N., and Enikolopov G. (1996) Nitric oxide regulates cell proliferation during Drosophila development. Cell 87, 639–649.
Bredt D. S. and Snyder S. H. (1994) Transient nitric oxide synthase neurons in embryonic cerebral cortical plate, sensory ganglia, and olfactory epithelium. Neuron 13, 301–313.
Black S. M., Bedolli M. A., Martinez S., Bristow J. D., Ferriero D. M., and Soifer S. J. (1995) Expression of neuronal nitric oxide synthase corresponds to regions of selective vulnerability to hypoxia-ischemia in the developing rat central nervous system. Neurobiol. Dis. 2, 145–155.
Roskams A. J., Bredt D. S., Dawson T. M., and Ronnett G. V. (1994) Nitric oxide mediates the formation of synaptic connections in developing and regenerating olfactory receptor neurons. Neuron 13, 289–299.
Giuili G., Luzi A., Poyard M., and Guellaen G. (1994) Expression of mouse brain soluble guanylate cyclase and NO synthase during ontogeny. Brain Res. Dev. Brain Res. 81, 269–283.
Blottner D., Grozdanovic Z., and Gossrau R. (1995) Histochemistry of nitric oxide synthase in the nervous system. Histochem. J. 27, 785–811.
Keilhoff G., Seidel B., Noack H., Tischmeyer W., Stanek D., and Wolf G. (1996) Patterns of nitric oxide synthase at the messenger RNA and protein levels during early rat brain development. Neuroscience 75, 1193–1201.
Foster J. A. and Phelps P. E. (2000) Neurons expressing NADPH-diaphorase in the developing human spinal cord. J. Comp. Neurol. 427, 417–427.
Tanaka M., Yoshida S., Yano M., and Hanaoka F. (1994) Roles of endogenous nitric oxide in cerebellar cortical development in slice cultures. Neuroreport 5, 2049–2052.
Wang W., Nakayama T., Inoue N., and Kato T. (1998) Quantitative analysis of nitric oxide synthase expressed in developing and differentiating rat cerebellum. Dev. Brain Res. 111, 65–75.
Virgili M., Monti B., LoRusso A., Bentivogli M., and Contestible A. (1999) Developmental effects of in vivo and in vitro inhibition of nitric oxide synthase neurons. Brain Res. 839, 164–172.
Peunova N. and Enikolopov G. (1995) Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells. Nature 375, 68–73.
Huber K. A., Krieglstein K., and Unsicker K. (1995) The neurotrophins BDNF, NT-3 and -4, but not NGF, TGF-beta 1 and GDNF, increase the number of NADPH-diaphorase reactive neurons in rat spinal cord cultures. Neuroscience 69, 771–779.
Sheehy A. M., Phung Y. T., Riemer R. K., and Black S. M. (1997) Growth factor induction of nitric oxide synthase in rat pheochromoctytoma cells. Brain Res. Mol. Brain Res. 52, 71–77.
Morbidelli L., Chang C. H., Douglas J. G., Granger H. J., Ledda F., and Ziche M. (1996) Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am. J. Physiol. 270, 411–415.
van der Zee R., Murohara T., Luo Z., Zollmann F., Passeri J., Lekutat C., et al. (1997) Vascular endothelial growth factor/vascular permeability factor augments nitric oxide release from quiescent rabbit and human vascular endothelium. Circulation 95, 1030–1037.
Cha M-S., Lee M-J., Je G-H., and Kwak J-Y. (2001) Endogenous production of nitric oxide by vascular endothelial growth factor downregulates proliferation of choriocarcinoma cells. Biochem. Biophys. Res. Comm. 282, 1061–1066.
Ghigo D., Priotto C., Migliorino D., Geromin D., Franchino C., Todde R., et al. (1998) Retinoic acid-induced differentiation in a human neuroblastoma cell line is associated with an increase in nitric oxide synthesis. J. Cell Physiol. 174, 99–106.
Cote F., Laflamme L., Payet M. D., and Gallo-Payet N. (1998) Nitric oxide, a new second messenger involved in the action of angiotensin II on neuronal differentiation of NG108-15 cells. Endocr. Res. 24, 403–407.
Gendron L., Cote F., Payet M. D., and Gallo-Payet N. (2002) Nitric oxide and cyclic GMP are involved in angiotensin II AT (2) receptor effects on neurite outgrowth in NG108-15 cells. Neuroendocrinology 75, 70–81.
Bulseco D. A., Poluha W., Schonhoff C. M., Daou M. C., Condon P. J., and Ross A. H. (2001) Cell-cycle arrest in TrkA-expressing NIHT3T cells involves nitric oxide synthase. J. Cell Biochem. 81, 193–204.
Schonhoff C. M., Bulseco D. A., Brancho D. N., Parada L. F., and Ross A. H. (2001) The Ras-ERK pathway is required for the induction of neuronal nitric oxide synthase in differentiating PC12 cells. J. Neurochem. 78, 631–639.
Truman J. W. (1996) Steroid receptors and nervous system metamorphosis in insects. Dev. Neurosci. 18, 87–101.
Champlin D. T. and Truman J. W. (1998) Ecdysteroids control cell proliferation during optic lobe neurogenesis of the moth, Manduca sexta. Development 125, 269–277.
Champlin D. T. and Truman J. W. (2000) Ecdysteroid coordinates optic lobe neurogenesis via a nitric oxide signaling pathway. Development 127, 3543–3551.
Gibbs S. M., Ngai J., Ekker S., and McLoon S. C. (2001) Regulation of ventral spinal cod development in zebrafish by nitric oxide and cyclic GMP. Soc. Neurosci. Abstr. Vol. 27.
Parisi M. J. and Lin H. (1998) The role of the hedgehog/patched signaling pathway in epithelial stem cell proliferation: from fly to human. Cell Res. 8, 15–21.
Villavicencio E. H., Walterhouse D. O., and Iannaccone P. M. (2000) The sonic hedgehogpatched-gli pathway in human development and disease. Am. J. Hum. Genet. 67, 1047–1054.
Lois C. and Alvarez-Buylla A. (1993) Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc. Natl. Acad. Sci. USA 90, 2074–2077.
Morshead C. M., Reynolds B. A., Craig C. G., McBurney M. W., Staines W. A., Morassutti D., et al. (1994) Neural stem cells in the adult mammalian forebrain. Neuron 13, 1071–1082.
Eriksson P. S., Perfilieva E., Bjork-Eriksson T., Alborn A.-M., Nordborg C., Peterson D. A., et al. (1998) Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317.
Doetch F., Caille I., Lim D. A., Garcia-Verdugo J. M., and Alvarez-Buylla. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716.
Lois C. and Alvarez-Buylla A. (1994) Long-distance neuronal migration in the adult mammalian brain. Science 264, 1145–1148.
Lois C., Garcia-Verdugo J. M., and Alvarez-Buylla A. (1996) Chain migration of neuronal precursors. Science 271, 978–981.
Moreno-Lopez B., Noval J. A., Gonzalez-Bonet L. G., and Estrada C. (2000) Morphological bases for a role of nitric oxide in adult neurogenesis. Brain Res. 869, 244–250.
Lopez-Figuero M. O., Itoi K., and Watson S. J. (1998) Regulation of nitric oxide synthase messenger RNA expression in the rat hippocampus by glucocorticoids. Neuroscience 87, 439–446.
Park C., Kang M., Kwon Y. K., Chung J. H., Ahn H., and Huh Y. (2001) Inhibition of neuronal nitric oxide synthase enhances cell proliferation in the dentate gyrus of the adrenalectomized rat. Neurosci. Lett. 309, 9–12.
Fanburg B. L. and Lee S-L. (1997) A new role for an old molecule: serotonin as a mitogen. Am. J. Physiol. 272, 795–806.
Brezun J. M. and Daszuta A. (1999) Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89, 999–1002.
Garg U. C. and Hassid A. (1990) Nitric oxide-generating vasodilators inhibit mitogenesis and proliferation of BALB/C 3T3 fibroblasts by a cyclic GMP-independent mechanism. Biochem. Biophys. Res. Commun. 171, 474–479.
Phung Y. T., Bekker J. M., Hallmark O. G., and Black S. M. (1999) Both neuronal NO synthase and nitric oxide are required for PC12 cell differentiation: and cGMP independent pathway. Brain Res. Mol. Brain Res. 64, 165–178.
Ishida A., Sasaguri T., Miwa Y., Kosaka C., Taba Y., and Abumiya T. (1999) Tumor suppressor p53 but not cGMP mediates NO-induced expression of p21Waf1/Cip1/Sdi1 in vascular smooth muscle cells. Mol. Pharm. 56, 938–946.
Young D. V., Serebryanik D., Janero D. R., and Tam S. W. (2000) Suppression of proliferation of human coronary artery smooth muscle cells by the nitric oxide donor S-nitrosoglutathione, is cGMP-independent. Mol. Cell Biol. Res. Commun. 4, 32–36.
Hatakeyama M. and Weinberg R. A. (1995) The role of RB in cell cycle control. Prog. Cell Cycle Res. 1, 9–19.
Yan G. Z. and Ziff E. B. (1997) Nerve growth factor induces transcription of the p21 Waf1/CIP1 and cyclin D genes in PC12 cells by activating the Sp1 transcription factor. J. Neurosci. 17, 6122–6132.
Poluha W., Poluha D. K., Chang B., Crosbie N. E., Schonhoff C. M., Kilpatrick D. L., et al. (1996) The cyclin-dependent kinase inhibitor p21 (Waf1) is required for survival of differentiating neuroblastoma cells. Mol. Cell. Biol. 16, 1335–1341.
Ko L. J. and Prives C. (1996) p53: puzzle and paradigm. Genes Dev. 10, 1054–1072.
Forrester K., Ambs S., Lupold S. E., Kapust R. B., Spillare E. A., Weinberg W. C., et al. (1996) Nitric oxide-induced p53 accumulation and regulation of inducible nitric oxide synthase expression by wild-type p53. Proc. Natl. Acad. Sci. USA 93, 2442–2447.
el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., et al. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825.
Kuzin B., Regulski M., Stasic Y., Scheinker V., Tully T., and Enikolopov G. (2000) Nitric oxide interacts with the retinoblastoma pathway to control eye development in Drosophila. Curr. Biol. 10, 459–462.
Du W., Vidal M., Xie J. E., and Dyson N. (1996) RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. Genes Dev. 10, 1206–1218.
Dyson N. (1998) The regulation of E2F by pRB-family proteins. Genes Dev. 12, 2245–2262.
Weinberger B., Laskin D. L., Heck D. E., and Laskin J. D. (2001) The toxicology of inhaled nitric oxide. Toxicol. Sci. 59, 5–16.
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Gibbs, S.M. Regulation of neuronal proliferation and differentiation by nitric oxide. Mol Neurobiol 27, 107–120 (2003). https://doi.org/10.1385/MN:27:2:107
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DOI: https://doi.org/10.1385/MN:27:2:107