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Vol. 17, No. 4, 2009
Issue release date: September 2009
Section title: Paper
Neurosignals 2009;17:255–264

Effects of Bone Morphogenic Proteins on Neural Precursor Cells and Regulation during Central Nervous System Injury

Sabo J.K. · Kilpatrick T.J. · Cate H.S.
Centre for Neuroscience and Florey Neuroscience Institutes, The University of Melbourne, Parkville, Vic., Australia
email Corresponding Author

Holly S. Cate

Centre for Neuroscience, The University of Melbourne

Melbourne, Vic. 3010 (Australia)

Tel. +61 3 8344 7318, Fax +61 3 9347 0446



  1. Tsumaki N, Yoshikawa H: The role of bone morphogenetic proteins in endochondral bone formation. Cytokine Growth Factor Rev 2005;16:279–285.
  2. Liu A, Niswander LA: Bone morphogenetic protein signalling and vertebrate nervous system development. Nat Rev Neurosci 2005;6:945–954.
  3. Mehler MF, Mabie PC, Zhang D, Kessler JA: Bone morphogenetic proteins in the nervous system. Trends Neurosci 1997;20:309–317.
  4. Chen HL, Panchision DM: Concise review: bone morphogenetic protein pleiotropism in neural stem cells and their derivatives – alternative pathways, convergent signals. Stem Cells 2007;25:63–68.
  5. Kingsley DM: The TGF-β superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 1994;8:133–146.
  6. Xiao YT, Xiang LX, Shao JZ: Bone morphogenetic protein. Biochem Biophys Res Commun 2007;362:550–553.
  7. Massague J: TGF-β signal transduction. Annu Rev Biochem 1998;67:753–791.
  8. Itoh S, Itoh F, Goumans MJ, Ten Dijke P: Signaling of transforming growth factor-β family members through Smad proteins. Eur J Biochem 2000;267:6954–6967.
  9. Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, Miyazono K, Taga T: Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 1999;284:479–482.
  10. Rajan P, Panchision DM, Newell LF, McKay RD: BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. J Cell Biol 2003;161:911–921.
  11. Balemans W, Van Hul W: Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev Biol 2002;250:231–250.
  12. Zimmerman LB, De Jesus-Escobar JM, Harland RM: The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 1996;86:599–606.
  13. Hata A, Lagna G, Massague J, Hemmati-Brivanlou A: Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 1998;12:186–197.
  14. Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH: A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 1999;400:687–693.
  15. Moren A, Imamura T, Miyazono K, Heldin CH, Moustakas A: Degradation of the tumor suppressor Smad4 by WW and HECT domain ubiquitin ligases. J Biol Chem 2005;280:22115–22123.
  16. Murakami G, Watabe T, Takaoka K, Miyazono K, Imamura T: Cooperative inhibition of bone morphogenetic protein signaling by Smurf1 and inhibitory Smads. Mol Biol Cell 2003;14:2809–2817.
  17. Zhang D, Mehler MF, Song Q, Kessler JA: Development of bone morphogenetic protein receptors in the nervous system and possible roles in regulating trkC expression. J Neurosci 1998;18:3314–3326.
  18. Mabie PC, Mehler MF, Kessler JA: Multiple roles of bone morphogenetic protein signaling in the regulation of cortical cell number and phenotype. J Neurosci 1999;19:7077–7088.
  19. Gross RE, Mehler MF, Mabie PC, Zang Z, Santschi L, Kessler JA: Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron 1996;17:595–606.
  20. Miller RH, Dinsio K, Wang R, Geertman R, Maier CE, Hall AK: Patterning of spinal cord oligodendrocyte development by dorsally derived BMP4. J Neurosci Res 2004;76:9–19.
  21. Lim DA, Tramontin AD, Trevejo JM, Herrera DG, Garcia-Verdugo JM, Alvarez-Buylla A: Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 2000;28:713–726.
  22. Colak D, Mori T, Brill MS, Pfeifer A, Falk S, Deng C, Monteiro R, Mummery C, Sommer L, Gotz M: Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells. J Neurosci 2008;28:434–446.
  23. Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A: Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 1997;17:5046–5061.
  24. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A: Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999;97:703–716.
  25. Lois C, Alvarez-Buylla A: Long-distance neuronal migration in the adult mammalian brain. Science 1994;264:1145–1148.
  26. Doetsch F, Alvarez-Buylla A: Network of tangential pathways for neuronal migration in adult mammalian brain. Proc Natl Acad Sci USA 1996;93:14895–14900.
  27. Nakashima K, Takizawa T, Ochiai W, Yanagisawa M, Hisatsune T, Nakafuku M, Miyazono K, Kishimoto T, Kageyama R, Taga T: BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc Natl Acad Sci USA 2001;98:5868–5873.
  28. Mathieu C, Sii-Felice K, Fouchet P, Etienne O, Haton C, Mabondzo A, Boussin FD, Mouthon MA: Endothelial cell-derived bone morphogenetic proteins control proliferation of neural stem/progenitor cells. Mol Cell Neurosci 2008;38:569–577.
  29. Bonaguidi MA, McGuire T, Hu M, Kan L, Samanta J, Kessler JA: LIF and BMP signaling generate separate and discrete types of GFAP-expressing cells. Development 2005;132:5503–5514.
  30. Kasai M, Satoh K, Akiyama T: Wnt signaling regulates the sequential onset of neurogenesis and gliogenesis via induction of BMPs. Genes Cells 2005;10:777–783.
  31. Samanta J, Kessler JA: Interactions between ID and OLIG proteins mediate the inhibitory effects of BMP4 on oligodendroglial dif- ferentiation. Development 2004;131:4131–4142.
  32. Hollnagel A, Oehlmann V, Heymer J, Ruther U, Nordheim A: Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells. J Biol Chem 1999;274:19838–19845.
  33. Ying QL, Nichols J, Chambers I, Smith A: BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 2003;115:281–292.
  34. Pringle NP, Richardson WD: A singularity of PDGF alpha-receptor expression in the dorsoventral axis of the neural tube may define the origin of the oligodendrocyte lineage. Development 1993;117:525–533.
  35. Soula C, Danesin C, Kan P, Grob M, Poncet C, Cochard P: Distinct sites of origin of oligodendrocytes and somatic motoneurons in the chick spinal cord: oligodendrocytes arise from Nkx2.2-expressing progenitors by a Shh-dependent mechanism. Development 2001;128:1369–1379.
  36. Mekki-Dauriac S, Agius E, Kan P, Cochard P: Bone morphogenetic proteins negatively control oligodendrocyte precursor specification in the chick spinal cord. Development 2002;129:5117–5130.
  37. Weible MW 2nd, Chan-Ling T: Phenotypic characterization of neural stem cells from human fetal spinal cord: synergistic effect of LIF and BMP4 to generate astrocytes. Glia 2007;55:1156–1168.
  38. Samanta J, Burke GM, McGuire T, Pisarek AJ, Mukhopadhyay A, Mishina Y, Kessler JA: Bmpr1a signaling determines numbers of oligodendrocytes and calbindin-expressing interneurons in the cortex. J Neurosci 2007;27:7397–7407.
  39. Gomes WA, Mehler MF, Kessler JA: Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Dev Biol 2003;255:164–177.
  40. Grinspan JB, Edell E, Carpio DF, Beesley JS, Lavy L, Pleasure D, Golden JA: Stage-specific effects of bone morphogenetic proteins on the oligodendrocyte lineage. J Neurobiol 2000;43:1–17.
  41. Grinspan JB, Stern JL, Pustilnik SM, Pleasure D: Cerebral white matter contains PDGF-responsive precursors to O2A cells. J Neurosci 1990;10:1866–1873.
  42. Raff MC, Miller RH, Noble M: A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 1983;303:390–396.
  43. Raff MC: Glial cell diversification in the rat optic nerve. Science 1989;243:1450–1455.
  44. Mabie PC, Mehler MF, Marmur R, Papavasiliou A, Song Q, Kessler JA: Bone morphogenetic proteins induce astroglial differentiation of oligodendroglial-astroglial progen- itor cells. J Neurosci 1997;17:4112–4120.
  45. Kondo T, Raff M: Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 2000;289:1754–1757.
  46. Kondo T, Raff MC: A role for noggin in the development of oligodendrocyte precursor cells. Dev Biol 2004;267:242–251.
  47. Sim FJ, Lang JK, Waldau B, Roy NS, Schwartz TE, Pilcher WH, Chandross KJ, Natesan S, Merrill JE, Goldman SA: Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation. Ann Neurol 2006;59:763–779.
  48. Woodruff RH, Tekki-Kessaris N, Stiles CD, Rowitch DH, Richardson WD: Oligodendrocyte development in the spinal cord and telencephalon: common themes and new perspectives. Int J Dev Neurosci 2001;19:379–385.
  49. Scherer SS, Braun PE, Grinspan J, Collarini E, Wang DY, Kamholz J: Differential regulation of the 2′,3′-cyclic nucleotide 3′-phosphodiesterase gene during oligodendrocyte development. Neuron 1994;12:1363–1375.
  50. Cheng X, Wang Y, He Q, Qiu M, Whittemore SR, Cao Q: Bone morphogenetic protein signaling and Olig1/2 interact to regulate the differentiation and maturation of adult oligodendrocyte precursor cells. Stem Cells 2007;25:3204–3214.
  51. See J, Zhang X, Eraydin N, Mun SB, Mamontov P, Golden JA, Grinspan JB: Oligodendrocyte maturation is inhibited by bone morphogenetic protein. Mol Cell Neurosci 2004;26:481–492.
  52. See J, Mamontov P, Ahn K, Wine-Lee L, Crenshaw EB 3rd, Grinspan JB: BMP signaling mutant mice exhibit glial cell maturation defects. Mol Cell Neurosci 2007;35:171–182.
  53. Bonaguidi MA, Peng CY, McGuire T, Falciglia G, Gobeske KT, Czeisler C, Kessler JA: Noggin expands neural stem cells in the adult hippocampus. J Neurosci 2008;28:9194–9204.
  54. Mizuguchi R, Sugimori M, Takebayashi H, Kosako H, Nagao M, Yoshida S, Nabeshima Y, Shimamura K, Nakafuku M: Combinatorial roles of Olig2 and Neurogenin2 in the coordinated induction of pan-neuronal and subtype-specific properties of motoneurons. Neuron 2001;31:757–771.
  55. Zhao C, Fancy SP, Magy L, Urwin JE, Franklin RJ: Stem cells, progenitors and myelin repair. J Anat 2005;207:251–258.
  56. Fuller ML, DeChant AK, Rothstein B, Caprariello A, Wang R, Hall AK, Miller RH: Bone morphogenetic proteins promote gliosis in demyelinating spinal cord lesions. Ann Neurol 2007;62:288–300.
  57. Ara J, See J, Mamontov P, Hahn A, Bannerman P, Pleasure D, Grinspan JB: Bone morphogenetic proteins 4, 6, and 7 are up-regulated in mouse spinal cord during exper- imental autoimmune encephalomyelitis. J Neurosci Res 2008;86:125–135.
  58. Deininger M, Meyermann R, Schluesener H: Detection of two transforming growth factor-β-related morphogens, bone morphogenetic proteins-4 and -5, in RNA of multiple sclerosis and Creutzfeldt-Jakob disease lesions. Acta Neuropathol 1995;90:76–79.
  59. Setoguchi T, Yone K, Matsuoka E, Takenouchi H, Nakashima K, Sakou T, Komiya S, Izumo S: Traumatic injury-induced BMP7 expression in the adult rat spinal cord. Brain Res 2001;921:219–225.
  60. Setoguchi T, Nakashima K, Takizawa T, Yanagisawa M, Ochiai W, Okabe M, Yone K, Komiya S, Taga T: Treatment of spinal cord injury by transplantation of fetal neural precursor cells engineered to express BMP inhibitor. Exp Neurol 2004;189:33–44.
  61. Hampton DW, Asher RA, Kondo T, Steeves JD, Ramer MS, Fawcett JW: A potential role for bone morphogenetic protein signalling in glial cell fate determination following adult central nervous system injury in vivo. Eur J Neurosci 2007;26:3024–3035.
  62. Enzmann GU, Benton RL, Woock JP, Howard RM, Tsoulfas P, Whittemore SR: Consequences of noggin expression by neural stem, glial, and neuronal precursor cells engrafted into the injured spinal cord. Exp Neurol 2005;195:293–304.
  63. Chang CF, Lin SZ, Chiang YH, Morales M, Chou J, Lein P, Chen HL, Hoffer BJ, Wang Y: Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats. Stroke 2003;34:558–564.
  64. Liu Y, Belayev L, Zhao W, Busto R, Saul I, Alonso O, Ginsberg MD: The effect of bone morphogenetic protein-7 (BMP-7) on functional recovery, local cerebral glucose utilization and blood flow after transient focal cerebral ischemia in rats. Brain Res 2001;905:81–90.
  65. Chou J, Harvey BK, Chang CF, Shen H, Morales M, Wang Y: Neuroregenerative effects of BMP7 after stroke in rats. J Neurol Sci 2006;240:21–29.
  66. Talbott JF, Cao Q, Enzmann GU, Benton RL, Achim V, Cheng XX, Mills MD, Rao MS, Whittemore SR: Schwann cell-like differentiation by adult oligodendrocyte precursor cells following engraftment into the demyelinated spinal cord is BMP-dependent. Glia 2006;54:147–159.
  67. Zhang Z, Trautmann K, Artelt M, Burnet M, Schluesener HJ: Bone morphogenetic protein-6 is expressed early by activated astrocytes in lesions of rat traumatic brain injury. Neuroscience 2006;138:47–53.