title: The α crystallin domain of small heat shock protein b8 (Hspb8) acts as survival and differentiation factor in adult hippocampal neurogenesis.
abstract: Adult hippocampal neurogenesis is to a large degree controlled at the level of cell survival, and a number of potential mediators of this effect have been postulated. Here, we investigated the small heat shock protein Hspb8, which, because of its pleiotropic prosurvival effects in other systems, was considered a particularly promising candidate factor. Hspb8 is, for example, found in plaques of Alzheimer disease but exerts neuroprotective effects. We found that expression of Hspb8 increased during differentiation in vitro and was particularly associated with later stages (48-96 h) of differentiation. Gain-of-function and loss-of-function experiments supported the hypothesis that Hspb8 regulates cell survival of new neurons in vitro. In the dentate gyrus of adult mice in vivo, lentiviral overexpression of Hspb8 doubled the surviving cells and concomitantly promoted differentiation and net neurogenesis without affecting precursor cell proliferation. We also discovered that the truncated form of the crystallin domain of Hspb8 was sufficient to affect cell survival and neuronal differentiation in vitro and in vivo. Precursor cell experiments in vitro revealed that Hspb8 increases the phosphorylation of Akt and suggested that the prosurvival effect can be produced by a cell-autonomous mechanism. Analysis of hippocampal Hspb8 expression in mice of 69 strains of the recombinant inbred set BXD revealed that Hspb8 is a cis-acting gene whose expression was associated with clusters of transcript enriched in genes linked to growth factor signaling and apoptosis. Our results strongly suggest that Hspb8 and its α-crystallin domain might act as pleiotropic prosurvival factor in the adult hippocampus.
authors.affiliation: Laboratory of Neurogenesis, Division of Clinical Investigations, National Institute of Psychiatry Ramón de la Fuente Muñiz, 14370 México, DF México.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ramírez-Rodríguez
authors.forename: Harish
authors.initials: H
authors.lastname: Babu
authors.forename: Friederike
authors.initials: F
authors.lastname: Klempin
authors.forename: Olga
authors.initials: O
authors.lastname: Krylyshkina
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Rupert W
authors.initials: RW
authors.lastname: Overall
authors.forename: Zeina
authors.initials: Z
authors.lastname: Nicola
authors.forename: Klaus
authors.initials: K
authors.lastname: Fabel
authors.forename: Gerd
authors.initials: G
authors.lastname: Kempermann
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival; D019295:Computational Biology; D018891:Dentate Gyrus / Q000166:cytology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D050888:Heat-Shock Proteins, Small / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D038201:alpha-Crystallins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050888:Heat-Shock Proteins, Small; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D038201:alpha-Crystallins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine
references.citation: Cardiovasc Drug Rev. 2007 Spring;25(1):14-29
references.pmid: 17445085
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: Cell. 2010 Jul 9;142(1):39-51
references.pmid: 20603013
references.citation: J Neurochem. 2005 Aug;94(4):943-56
references.pmid: 15992382
references.citation: Neuron. 2002 Jun 13;34(6):945-60
references.pmid: 12086642
references.citation: Brain Res Rev. 2008 Mar;57(2):332-41
references.pmid: 17669502
references.citation: Hum Gene Ther. 2006 Jun;17(6):635-50
references.pmid: 16776572
references.citation: Neuropathol Appl Neurobiol. 2012 Feb;38(1):39-53
references.pmid: 21696420
references.citation: Circ Res. 2006 Feb 3;98(2):280-8
references.pmid: 16373598
references.citation: Cell Stress Chaperones. 2005 Spring;10(1):46-58
references.pmid: 15832947
references.citation: Circ Res. 2009 Apr 10;104(7):887-95
references.pmid: 19246680
references.citation: Mol Psychiatry. 2013 Sep;18(9):993-1005
references.pmid: 22925833
references.citation: Neuron. 1996 Sep;17(3):401-11
references.pmid: 8816704
references.citation: Neuropsychopharmacology. 2009 Aug;34(9):2180-91
references.pmid: 19421166
references.citation: Nucleic Acids Res. 2000 Sep 15;28(18):3442-4
references.pmid: 10982861
references.citation: Front Neurosci. 2009 Nov 10;3:55
references.pmid: 20582282
references.citation: J Neurochem. 2006 Oct;99(2):570-81
references.pmid: 16879711
references.citation: Hippocampus. 2012 Apr;22(4):861-8
references.pmid: 21692136
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: J Neurosci Res. 2011 Feb;89(2):162-75
references.pmid: 21162124
references.citation: Cell. 2008 Jan 11;132(1):27-42
references.pmid: 18191218
references.citation: J Comp Neurol. 2000 Oct 2;425(4):479-94
references.pmid: 10975875
references.citation: Hum Mol Genet. 2009 Apr 1;18(7):1190-9
references.pmid: 19129171
references.citation: Biochem J. 2009 Dec 14;425(1):e1-3
references.pmid: 20001957
references.citation: Neurobiol Dis. 2009 May;34(2):366-74
references.pmid: 19233274
references.citation: Eur J Neurosci. 2008 May;27(10):2493-500
references.pmid: 18547240
references.citation: Neuron. 2010 Nov 18;68(4):682-94
references.pmid: 21092858
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 May;294(5):R1693-703
references.pmid: 18287218
references.citation: Trends Biochem Sci. 2004 May;29(5):233-42
references.pmid: 15130559
references.citation: Autophagy. 2009 Apr;5(3):428-9
references.pmid: 19202352
references.citation: Am J Pathol. 2009 Nov;175(5):2076-88
references.pmid: 19808651
references.citation: Front Neuroendocrinol. 2009 Aug;30(3):343-57
references.pmid: 19361542
references.citation: J Biol Chem. 2010 Nov 26;285(48):37811-22
references.pmid: 20858900
references.citation: BMC Neurosci. 2009 Jan 13;10:2
references.pmid: 19144149
references.citation: Neuroscience. 2008 May 2;153(2):483-91
references.pmid: 18384969
references.citation: Biochem J. 2009 Dec 14;425(1):245-55
references.pmid: 19845507
references.citation: Front Neurosci. 2009 Sep 30;3:49
references.pmid: 20582276
references.citation: Front Neurosci. 2011 Jul 14;5:89
references.pmid: 21811434
references.citation: Autophagy. 2009 Jan;5(1):120-1
references.pmid: 19001866
references.citation: Acta Neuropathol. 2006 Feb;111(2):139-49
references.pmid: 16485107
references.citation: Mol Cell Biochem. 2004 Oct;265(1-2):71-8
references.pmid: 15543936
references.citation: Curr Biol. 2010 Jan 26;20(2):143-8
references.pmid: 20060297
references.citation: J Neurosci. 2012 Mar 7;32(10):3376-87
references.pmid: 22399759
references.citation: J Biol Chem. 2009 Feb 27;284(9):5523-32
references.pmid: 19114712
references.citation: J Neurosci. 1999 Sep 1;19(17):7476-85
references.pmid: 10460254
references.citation: Hum Mol Genet. 2010 Sep 1;19(17):3440-56
references.pmid: 20570967
references.citation: Nat Genet. 2004 Jun;36(6):597-601
references.pmid: 15122253
references.citation: PLoS One. 2009;4(4):e5351
references.pmid: 19399179
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):780-5
references.pmid: 16407118
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2669-74
references.pmid: 20133768
references.citation: J Biol Chem. 2008 Jan 18;283(3):1437-1444
references.pmid: 18006506
references.citation: Curr Protoc Bioinformatics. 2009 Sep;Chapter 13:Unit 13.11
references.pmid: 19728287
references.citation: Trends Neurosci. 2004 Aug;27(8):447-52
references.pmid: 15271491
references.citation: Nucleic Acids Res. 2011 Jan;39(Database issue):D561-8
references.pmid: 21045058
references.citation: J Biol Chem. 1977 Feb 10;252(3):1102-6
references.pmid: 320200
references.citation: J Neurosci. 2006 Apr 5;26(14):3798-804
references.pmid: 16597733
references.citation: Ann Neurol. 1997 Apr;41(4):512-20
references.pmid: 9124809
references.citation: Autophagy. 2008 Feb;4(2):237-9
references.pmid: 18094623
references.citation: J Pineal Res. 2011 Jan;50(1):29-37
references.pmid: 20880317
references.citation: PLoS Biol. 2008 Nov 11;6(11):e272
references.pmid: 18998770
references.citation: J Neurochem. 2010 Jun;113(5):1092-100
references.pmid: 20067574
references.citation: Hum Mol Genet. 2010 Aug 15;19(16):3254-65
references.pmid: 20538880
references.citation: Exp Neurol. 2008 Mar;210(1):154-63
references.pmid: 18096160
references.citation: J Neurosci. 2007 May 2;27(18):4894-901
references.pmid: 17475797
references.citation: Eur J Neurosci. 2006 Oct;24(7):1850-6
references.pmid: 17040481
references.citation: Nature. 2005 Oct 27;437(7063):1370-5
references.pmid: 16251967
references.citation: Neuron. 2009 Sep 24;63(6):761-73
references.pmid: 19778506
references.citation: Cell. 2012 Mar 2;148(5):1051-64
references.pmid: 22385968
references.citation: Nature. 2011 Apr 28;472(7344):466-70
references.pmid: 21460835
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63
references.pmid: 21233418
references.citation: Ann Neurol. 2003 Mar;53(3):420-1; author reply 421
references.pmid: 12601720
references.citation: Mol Cell Biochem. 2011 Sep;355(1-2):47-55
references.pmid: 21526341