Noggin expands neural stem cells in the adult hippocampus.
New neurons are added to the adult hippocampus throughout life and contribute to cognitive functions, including learning and memory. It remains unclear whether ongoing neurogenesis arises from self-renewing neural stem cells (NSCs) or from multipotential progenitor cells that cannot self-renew in the hippocampus. This is primarily based on observations that neural precursors derived from the subventricular zone (SVZ) can be passaged long term, whereas hippocampal subgranular zone (SGZ) precursors are rapidly depleted by passaging. We demonstrate here that high levels of bone morphogenetic protein (BMP) signaling occur in hippocampal but not SVZ precursors in vitro, and blocking BMP signaling with Noggin is sufficient to foster hippocampal cell self-renewal, proliferation, and multipotentiality using single-cell clonal analysis. Moreover, NSC maintenance requires continual Noggin exposure, which implicates BMPs as crucial regulators of NSC aging. In vivo, Noggin is expressed in the adult dentate gyrus and limits BMP signaling in proliferative cells of the SGZ. Transgenic Noggin overexpression in the SGZ increases multiple precursor cell populations but proportionally increases the glial fibrillary acidic protein-positive cell population at the expense of other precursors, suggesting that Noggin acts on NSCs in vivo. To confirm this, we used a dual thymidine analog paradigm to repeatedly label slowly dividing cells over a long duration. We find that small populations of label-retaining cells exist in the SGZ and that Noggin overexpression increases their numbers. Thus, we propose that the adult hippocampus contains a population of NSCs, which can be expanded both in vitro and in vivo by blocking BMP signaling.
Bonaguidi
Michael A
MA
Davee Department of Neurology, Northwestern University's Feinberg School of Medicine, Chicago, Illinois 60611, USA. mbonagu1@jhmi.edu
Peng
Chian-Yu
CY
McGuire
Tammy
T
Falciglia
Gustave
G
Gobeske
Kevin T
KT
Czeisler
Catherine
C
Kessler
John A
JA
D053687:Adult Stem Cells / Q000187:drug effects / Q000502:physiology*; D000704:Analysis of Variance; D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D007065:Idoxuridine / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D019081:O Antigens / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D012794:Sialic Acids / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D001973:Bromodeoxyuridine; D002352:Carrier Proteins; D003857:Deoxyuridine; D005904:Glial Fibrillary Acidic Protein; D007065:Idoxuridine; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D039842:Neural Cell Adhesion Molecule L1; D016900:Neurofilament Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D019081:O Antigens; D010751:Phosphopyruvate Hydratase; D012794:Sialic Acids; D019098:Telomerase; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse; C079240:Mtap2 protein, mouse; C103469:polysialyl neural cell adhesion molecule; C012244:5-chloro-2'-deoxyuridine; C509187:Tert protein, mouse
Development. 2005 Dec;132(24):5503-14
16314487
J Neurosci. 1996 Feb 1;16(3):1091-100
8558238
Nat Genet. 2004 Aug;36(8):827-35
15258583
Science. 1996 Jul 12;273(5272):242-5
8662508
Science. 2000 Sep 8;289(5485):1754-7
10976069
Biochemistry (Mosc). 1997 Nov;62(11):1323-31
9467857
Annu Rev Neurosci. 2005;28:223-50
16022595
Neuron. 1994 Nov;13(5):1071-82
7946346
Cell. 1986 Jun 20;45(6):917-27
2871944
J Neurosci. 2002 Mar 1;22(5):1784-93
11880507
Nature. 2001 Mar 15;410(6826):372-6
11268214
Development. 1998 Jun;125(12):2251-61
9584124
J Cell Biol. 2003 Apr 14;161(1):169-86
12682089
Nature. 2003 Oct 9;425(6958):577-84
14534577
J Neurosci. 2008 Jan 9;28(2):434-46
18184786
J Neurosci. 2008 May 14;28(20):5240-7
18480280
Trends Neurosci. 2005 Nov;28(11):589-95
16153715
Science. 1988 Jul 1;241(4861):58-62
2898810
J Neurosci. 2004 Mar 3;24(9):2133-42
14999064
J Neurosci. 1997 May 15;17(10):3727-38
9133393
Am J Pathol. 2004 Sep;165(3):729-40
15331398
Brain Res Dev Brain Res. 2003 Dec 19;146(1-2):51-8
14643011
J Neurosci. 1997 Jul 1;17(13):5046-61
9185542
Cell. 2005 Jul 1;121(7):1109-21
15989959
J Comp Neurol. 1965 Jun;124(3):319-35
5861717
Mol Cell Neurosci. 1997;8(6):389-404
9143557
Dev Biol. 2002 Nov 15;251(2):221-40
12435354
J Comp Neurol. 2004 Oct 25;478(4):359-78
15384070
Science. 1992 Mar 27;255(5052):1707-10
1553558
Neuron. 2000 Dec;28(3):713-26
11163261
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11879-83
8524867
J Neurosci. 2005 Nov 23;25(47):10815-21
16306394
Dev Biol. 2003 Mar 1;255(1):164-77
12618141
Cell Stem Cell. 2007 Nov;1(5):515-28
18371391
J Neurosci. 1996 Mar 15;16(6):2027-33
8604047
Curr Opin Neurobiol. 2005 Oct;15(5):514-20
16144763
Nat Neurosci. 1999 Mar;2(3):260-5
10195219
Nat Neurosci. 2004 Nov;7(11):1233-41
15494728
Mol Cell Neurosci. 2003 Aug;23(4):693-702
12932448
Science. 1977 Sep 9;197(4308):1092-4
887941
Eur J Neurosci. 2007 Dec;26(11):3024-35
18028109
J Neurosci. 1999 May 1;19(9):3287-97
10212288
Dev Neurosci. 2005 Mar-Aug;27(2-4):93-9
16046842
J Neurosci. 2004 Feb 18;24(7):1726-33
14973255
Nature. 2002 Feb 28;415(6875):1030-4
11875571
J Neurosci. 1998 May 1;18(9):3206-12
9547229
PLoS One. 2007 Apr 25;2(4):e388
17460755
J Neurosci. 2006 Nov 15;26(46):12089-99
17108182
J Neurosci. 2001 Sep 15;21(18):7153-60
11549726
Radiat Res. 2004 Jul;162(1):39-47
15222778
J Cell Biol. 2004 May 24;165(4):575-89
15159421
Nature. 2005 Oct 27;437(7063):1370-5
16251967
Cell. 1999 Jun 11;97(6):703-16
10380923
Science. 2003 Aug 8;301(5634):805-9
12907793
Nat Med. 2003 Apr;9(4):439-47
12627226
Hippocampus. 2004;14(7):861-75
15382256
Sci STKE. 2002 Sep 24;2002(151):pe40
12297674