title: Sonic hedgehog pathway activation is induced by acute brain injury and regulated by injury-related inflammation.
abstract: The adult mammalian brain responds to injury by activating a program of cell proliferation during which many oligodendrocyte precursors, microglia, and some astrocytes proliferate. Another common response to brain injury is the induction of reactive gliosis, a process whereby dormant astrocytes undergo morphological changes and alter their transcriptional profiles. Although brain injury-induced reactive gliosis is concurrent with the proliferation of surrounding cells, a functional relationship between reactive gliosis and this cell proliferation has not been clearly demonstrated. Here, we show that the mitogen sonic hedgehog (SHH) is produced in reactive astrocytes after injury to the cerebral cortex and participates in regulating the proliferation of Olig2-expressing (Olig2(+)) cells after brain injury. Using a cortical freeze injury to induce reactive gliosis in a Gli-luciferase reporter mouse, we show that the SHH pathway is maximally active 3 d after brain injury and returns to baseline levels by 14 d. SHH expression parallels Gli activation and localizes to glial fibrillary acidic protein-expressing reactive astrocytes. Inhibition of the SHH pathway with cyclopamine blocks the Gli response and significantly reduces both the proliferating and overall number of Olig2(+) cells in the injured cortex. To provide mechanistic insight into SHH pathway activation in astrocytes, we show that proinflammatory stimuli activate SHH-expressing reactive astrocytes, whereas inhibition of inflammation-induced reactive gliosis by macrophage depletion abolishes SHH activation after brain injury and dampens cell proliferation after injury. Our data describes a unique reactive astrocyte-based, SHH-expressing niche formed in response to injury and inflammation that regulates the proliferation of Olig2(+) cells.
authors.affiliation: Department of Cancer Biology and Genetics and Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Nduka M
authors.initials: NM
authors.lastname: Amankulor
authors.forename: Dolores
authors.initials: D
authors.lastname: Hambardzumyan
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Pyonteck
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology*; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D000076104:Oligodendrocyte Transcription Factor 2; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053823:Hedgehog Proteins; D018836:Inflammation Mediators; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C512773:Olig2 protein, mouse; C465570:Shh protein, mouse
references.citation: Nature. 2005 Oct 6;437(7060):894-7
references.pmid: 16208373
references.citation: Proc Natl Acad Sci U S A. 2006 May 16;103(20):7853-8
references.pmid: 16682644
references.citation: Neurochem Int. 2005 Apr;46(5):381-9
references.pmid: 15737436
references.citation: Restor Neurol Neurosci. 2008;26(2-3):197-214
references.pmid: 18820411
references.citation: J Neurosci. 2008 Oct 22;28(43):10983-9
references.pmid: 18945906
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18183-8
references.pmid: 16330768
references.citation: Neuroscience. 2004;127(4):813-20
references.pmid: 15312894
references.citation: J Neurosci. 2008 Jul 9;28(28):7231-43
references.pmid: 18614693
references.citation: Development. 2001 Jul;128(13):2545-54
references.pmid: 11493571
references.citation: FASEB J. 2009 Jan;23(1):21-33
references.pmid: 18772349
references.citation: J Neurosci. 2007 Mar 7;27(10):2596-605
references.pmid: 17344397
references.citation: Biol Reprod. 2007 Aug;77(2):226-36
references.pmid: 17392501
references.citation: Cochrane Database Syst Rev. 2005 Jan 25;(1):CD000196
references.pmid: 15674869
references.citation: J Cereb Blood Flow Metab. 2008 Mar;28(3):468-81
references.pmid: 17726492
references.citation: Glia. 2004 May;46(4):380-90
references.pmid: 15095368
references.citation: Science. 1985 Apr 26;228(4698):497-9
references.pmid: 3872478
references.citation: J Neurochem. 2006 Feb;96(3):893-907
references.pmid: 16405499
references.citation: Nature. 1996 Nov 14;384(6605):129-34
references.pmid: 8906787
references.citation: Development. 2001 Feb;128(4):527-40
references.pmid: 11171336
references.citation: Cancer Res. 2008 Apr 1;68(7):2241-9
references.pmid: 18381430
references.citation: Restor Neurol Neurosci. 2007;25(1):65-76
references.pmid: 17473396
references.citation: Stem Cells. 2008 May;26(5):1221-30
references.pmid: 18323412
references.citation: Dev Biol. 2000 Nov 15;227(2):648-60
references.pmid: 11071781
references.citation: Neuron. 1999 Jun;23(2):297-308
references.pmid: 10399936
references.citation: J Immunol. 2004 May 15;172(10):6418-26
references.pmid: 15128833
references.citation: Development. 2005 Jan;132(2):335-44
references.pmid: 15604099
references.citation: Neurotoxicology. 2001 Oct;22(5):607-18
references.pmid: 11770882
references.citation: Lancet Neurol. 2008 Aug;7(8):728-41
references.pmid: 18635021
references.citation: Neuroscience. 2001;102(4):805-18
references.pmid: 11182244
references.citation: Brain Res. 2007 Jan 19;1129(1):43-52
references.pmid: 17169340
references.citation: J Neurosci. 2008 Jul 2;28(27):6904-13
references.pmid: 18596165
references.citation: J Neuropathol Exp Neurol. 2005 May;64(5):404-11
references.pmid: 15892298
references.citation: J Mol Neurosci. 2004;24(2):201-5
references.pmid: 15456933
references.citation: J Neurosci. 2004 Mar 3;24(9):2143-55
references.pmid: 14999065
references.citation: Development. 1997 Apr;124(7):1313-22
references.pmid: 9118802
references.citation: Development. 1998 Sep;125(18):3553-62
references.pmid: 9716521
references.citation: J Neuroinflammation. 2006 Jun 30;3:15
references.pmid: 16808851
references.citation: Nat Rev Neurosci. 2004 Feb;5(2):146-56
references.pmid: 14735117
references.citation: J Neurotrauma. 2000 Oct;17(10):927-38
references.pmid: 11063058
references.citation: J Neurosci Res. 2008 May 1;86(6):1199-208
references.pmid: 18058947
references.citation: J Clin Invest. 2004 May;113(9):1364-74
references.pmid: 15124028
references.citation: Exp Neurol. 2005 Mar;192(1):11-24
references.pmid: 15698615
references.citation: J Neurosci. 1988 Jul;8(7):2485-90
references.pmid: 2470873
references.citation: Nature. 2006 Aug 17;442(7104):823-6
references.pmid: 16799564
references.citation: Neurochem Res. 2004 Nov;29(11):2069-73
references.pmid: 15662841
references.citation: J Clin Invest. 2005 Jan;115(1):56-65
references.pmid: 15630444
references.citation: Ann Neurol. 2008 Oct;64(4):417-27
references.pmid: 18991353
references.citation: J Neurochem. 2004 Jun;89(5):1092-100
references.pmid: 15147501
references.citation: Brain Res. 1998 Jan 12;780(2):294-303
references.pmid: 9507169
references.citation: J Neuropathol Exp Neurol. 2001 Oct;60(10):961-71
references.pmid: 11589427
references.citation: J Neurosci. 2008 Oct 8;28(41):10434-42
references.pmid: 18842903
references.citation: Perspect Dev Neurobiol. 1994;2(3):269-74
references.pmid: 7850360
references.citation: Brain. 2006 Oct;129(Pt 10):2761-72
references.pmid: 16825202
references.citation: Nature. 1984 Mar 15-21;308(5956):274-5
references.pmid: 6700730