Cdk5 is essential for adult hippocampal neurogenesis
Diane C. Lagacea, David R. Benavidesa, Janice W. Kansya, Marina Mapellib, Paul Greengardc,1, James A. Bibba,
and Amelia J. Eischa,1
aDepartment of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070;bStructural Biology Unit,
Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, 20139 Milan, Italy; andcLaboratory of Molecular and Cellular
Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021
Contributed by Paul Greengard, October 9, 2008 (sent for review October 1, 2008)
The molecular factors regulating adult neurogenesis must be
understood to harness the therapeutic potential of neuronal stem
in embryonic corticogenesis, its function in adult neurogenesis is
unknown. Here, we assessed the role of Cdk5 in the generation of
dentate gyrus (DG) granule cell neurons in adult mice. Cre recom-
and their progeny in the DG subgranular zone (SGZ) prevented
maturation of new neurons. In addition, selective KO of Cdk5 from
mature neurons throughout the hippocampus reduced the number
of immature neurons. Furthermore, Cdk5 gene deletion specifically
from DG granule neurons via viral-mediated gene transfer also
of proliferating cells was unaffected, indicating that Cdk5 is nec-
essary for progression of adult-generated neurons to maturity.
This role for Cdk5 in neurogenesis was activating-cofactor specific,
as p35 KO but not p39 KO mice also had fewer immature neurons.
Thus, Cdk5 has an essential role in the survival, but not prolifer-
ation, of adult-generated hippocampal neurons through both
cell-intrinsic and cell-extrinsic mechanisms.
cyclin-dependent kinase ? dentate gyrus granule cell ? doublecortin ?
nestin-CreERT2 ? viral-mediated gene transfer
subgranular zone (SGZ) (1, 2). This process of adult neurogen-
esis is orchestrated by signaling intrinsic to the new cells as well
as extrinsic or microenvironmental influences in the SGZ niche
(2, 3). For example, the orphan nuclear receptor tailless intrin-
sically regulates stem cell proliferation (4) and neurogenesin-1
extrinsically regulates fate specification (5). In contrast to our
growing understanding of factors that regulate proliferating
cells, the identity and mechanisms of factors that regulate
immature neurons remain unclear (3). Elucidation of the intrin-
sic and extrinsic factors that mediate the formation of new
neurons is critical to understand normal brain development and
to realize the therapeutic potential of adult neurogenesis.
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed,
serine/threonine cyclin-dependent kinase family member. Its
activity is largely restricted to post-mitotic neurons of the central
nervous system (6) and depends on association with the non-
cyclin cofactors p35 and p39 (7, 8). Cdk5 plays a critical role in
neuronal migration during development and is highly enriched
in the hippocampus. Therefore, it might be predicted to be
important in the formation of immature neurons in the adult
hippocampus. This hypothesis is supported by the importance of
Cdk5 substrates, including nestin and doublecortin (DCX), in
adult neurogenesis (9–11). Here, we demonstrate that Cdk5 is
critical for adult hippocampal neurogenesis. Using several ap-
proaches, we show that ablation of the Cdk5 gene from either
SGZ stem cells or from mature dentate gyrus (DG) neurons
decreases the number of immature SGZ neurons. These findings
emphasize that Cdk5 regulates neurogenesis through both in-
trinsic and extrinsic mechanisms in the SGZ of the adult
n the adult brain, neural precursors give rise to immature
neurons which mature into granule cells in the hippocampal
Cdk5 Protein Is Located in Immature Neurons and Mature Granule
Neurons of the DG. Previous in situ hybridization and immunoblot
analyses reported high levels of Cdk5 in the embryonic and adult
DG (12–14). To identify which DG cells specifically express
Cdk5 in the adult, a Cdk5 monoclonal antibody (Ab) was
generated. Validation of the Ab demonstrated its specificity in
vitro and in vivo (see supporting information (SI) Fig. S1) and
localization of Cdk5 in adult hippocampal cells (Fig. 1A).
Interestingly, Cdk5 was not present in dividing stem-like and
progenitor cells, as demonstrated by the lack of colabeling of
Cdk5 and green fluorescent protein (GFP) in the SGZ of
nestin-GFP mice (Fig. 1B). In contrast, Cdk5 staining was
evident in a subpopulation (?10%) of ‘‘older’’ post-mitotic
immature DCX immunoreactive (DCX?) neurons (11), identi-
fied by their immature apical branching dendrites (15) (Fig. 1C).
As expected, Cdk5 was also expressed in almost all (approxi-
Cdk5 is not expressed at early stages of adult neurogenesis, but
in later stages, with most mature granule cell neurons expressing
Inducible Removal of Cdk5 from SGZ Stem Cells Prevents Adult
Hippocampal Neurogenesis. Cdk5?/?KO mice are perinatal lethal
(16), impeding examination of the role of Cdk5 in adult hip-
pocampal neurogenesis. Therefore, we created an inducible
nestin driven Cdk5 KO transgenic mouse (Cdk5 nKO) that
allows specific ablation of Cdk5 from nestin expressing progen-
itor cells and their progeny. Nestin-CreERT2/R26R-YFP (17)
mice were crossed with floxed Cdk5 (fCdk5) mice (18, 19) to
generate Cdk5 nKO mice (Fig. 2A). In these mice, the nestin
estrogen receptor (CreERT2) fusion protein in SGZ progenitors.
On administration of the estrogen congener tamoxifen (TAM),
CreERT2recombines DNA loxP sites, allowing YFP expression
and Cdk5 deletion in nestin expressing cells (Fig. 2A). In mice
harboring the WT Cdk5 gene, the number of recombined
(YFP?) SGZ cells doubled between 12 and 30 days post-TAM
(Fig. 2 B and C) because of the accumulation of recombined
dividing progenitor progeny (17). In contrast, there was no
change in YFP? SGZ cells in Cdk5 nKO mice between 12 and
30 days post-TAM (Fig. 2 B and C). Thus, removal of Cdk5 from
stem cells and their progeny prevents the increase in the number
of recombined cells 30 days post-TAM.
We hypothesized that the removal of Cdk5 reduced the
number of YFP? cells by preventing the maturation of DCX?
J.W.K., M.M., and A.J.E. performed research; J.W.K., M.M., P.G., J.A.B., and A.J.E. contrib-
uted new reagents/analytic tools; D.C.L. and A.J.E. analyzed data; and D.C.L., D.R.B., P.G.,
J.A.B., and A.J.E. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/
© 2008 by The National Academy of Sciences of the USA
November 25, 2008 ?
vol. 105 ?
no. 47 ?
cells into neurons because (i) WT and Cdk5 nKO mice did not
differ in the number of YFP? progenitor cells 12 days post-
TAM (Fig. 2C); (ii) Cdk5 is expressed in DCX? and mature
NeuN? SGZ cells (Fig. 1 C and D); and (iii) YFP?/NeuN?
neurons first appear 30 days post-TAM (17). Indeed WT mice
had mature (NeuN?) YFP? neurons 30 days post-TAM, but
Cdk5 nKO mice had ?1.5% YFP? cells expressing NeuN (Fig.
2D). This occurred without a change in the percentage of YFP?
cells that expressed DCX (WT ? 36.3%?4.7; nKO ?
32.1%?7.3). Together these findings suggest that the reduction
in number of mature neurons 30 days post-TAM in Cdk5 nKO
mice may be a result of enhanced cell death in the SGZ. In fact,
there were significantly more activated caspase 3 immunoreac-
tive (AC3?) SGZ cells at 30 days post-TAM in Cdk5 nKO mice
vs. WT controls (Fig. 2E). Furthermore, embryonic conditional
Cdk5 KO mice have no difference in subventricular zone pro-
liferation when examined at an early postnatal time point (20).
Thus, these data suggest a cell intrinsic effect, where Cdk5
expression in immature neurons is required for survival of
adult-generated dentate granule neurons.
Conditional CamKII-Cdk5 KO Mice and p35 KO Mice Have Fewer
Immature SGZ Neurons.Consideringthehighlevelofexpressionof
(21, 22), we next deleted Cdk5 from mature granule neurons and
evaluated proliferation and maturation. For this study CamKII-
Cre fCdk5 conditional knockout mice (cKO) were used (19).
Cdk5 cKO mice had less Cdk5 in the hippocampus when
compared with WT mice (WT ? 100 ? 21.6%, cKO ? 37.8 ?
16.2%; t(10)? 2.4, P ? 0.05; n ? 6 per group).
The fCdk5 cKO mice exhibited no difference in the number of
proliferating cells (Ki67?) compared with WT mice (Fig. 3A).
C). To confirm that recombination in the cKO mice only
occurred in mature granule cells, we bred cKO mice with
R26R-YFP reporter mice. A fraction of mature NeuN? granule
cells (39.9 ? 1.8%) were YFP? (Fig. 3E). Almost all YFP? cells
were NeuN?, but no YFP? cells were DCX? (Fig. 3D). These
results indicate that in addition to its intrinsic influence, Cdk5
plays an extrinsic role in the maturation of adult-generated SGZ
Mice lacking the Cdk5 activating cofactor p35 are viable (23)
our conditional KO mice. WT and p35 KO mice had similar
numbers of proliferating SGZ cells (Ki67?; Fig. 3F) but, inter-
estingly, there was a 30 ? 7% reduction in the number of
immature (DCX?) SGZ neurons in p35 KO mice compared
with WT mice (Fig. 3 G and H). In addition to p35, its homolog
p39 also activates Cdk5 and is present in comparable levels in
adult brain (12). However, analysis of p39 KO mice revealed no
significant neurogenic phenotype (data not shown). These data
the hippocampus. (A) Immunofluorescent detection of Cdk5 in dentate gyrus
(DG) granule cells, interneurons of the hilus, and dendrites and cell bodies of
CA1-CA3 neurons. (B) Cdk5 and GFP immunolabeling showing that GFP?
and DCX immunolabeling of SGZ showing Cdk5 in a subpopulation of DCX?
immature neurons (arrowhead). An arrow indicates a typical DCX? cell that
does not express Cdk5. (D) Cdk5 and NeuN immunolabeling illustrating that
almost all DG granule cells (NeuN?) also express Cdk5. (Scale bars: B, 60 ?m;
C, 30 ?m; D, 60 ?m.)
Localization of Cdk5 in postmitotic immature and mature neurons in
Diagram of genetic manipulations in the 3 mouse lines to create Cdk5 nKO
mice. (B) Immunofluorescent detection of YFP? (green) cells with nuclear
counterstaining (DAPI) in the SGZ of WT and Cdk5 nKO mice at 12 and 30 d
post-TAM with quantification (C:**, P ? 0.01 compared with 12 d WT,
two-way ANOVA; n ? 5–10 per group). (Scale bar, 60 ?m.) (D) Percent YFP?
P ? 0.05; n ? 6 per group).
www.pnas.org?cgi?doi?10.1073?pnas.0810137105Lagace et al.
neurons and indicate that the Cdk5/p35 complex predominantly
regulates adult SGZ neurogenesis.
Selective Deletion of Cdk5 in Mature DG Neurons Attenuates Neuro-
genesis. To further investigate the extrinsic role of Cdk5 in
hippocampal neurogenesis, Cdk5 was specifically removed from
postmitotic DG neurons via adeno-associated virus (AAV)-
cally infused unilaterally into the DG of R26R-YFP/fCdk5 mice
and histological analysis was conducted. Recombination, as
assessed by YFP expression 2 weeks after infusion, was evident
in anterior DG granule neurons and hilar interneurons (Fig. 4 A
and B). Viral-mediated transduction of the DG of R26R-YFP/
fCdk5 but not WT mice decreased the number of immature
(DCX?) neurons in the injected side by 21% compared with the
contralateral side (Fig. 4 C–E). As in our other models, prolif-
eration was the same between WT and fCdk5 mice (Fig. 4E).
These data underscore that ablation of Cdk5 from mature
neurons in the DG impedes the development of new SGZ
neurons in the absence of altering SGZ proliferation.
of the birth, migration, differentiation, survival, and functional
integration of new neurons in the granule cell layer (3). Within
a week of cell cycle exit, new hippocampal progenitors extend
dendrites toward the molecular layer, and within two weeks
extend their mossy fiber axons through the hilus to CA3 (3).
Within four weeks approximately half of the new cells in the
postnatal hippocampus have survived to integrate into the
granule cell layer circuitry, a process reminiscent of pruning
during embryogenesis (24). Progression through each stage is
achieved via intrinsic alterations within the differentiating and
migrating progenitors as well by a host of extrinsic factors in the
hippocampal niche (3). While neurogenesis research has the
potential for translation to clinical therapies aimed at cell
factors that govern cell survival and neuronal integration is
Cdk5 regulates actin dynamics, microtubule stability, cell
adhesion, axon guidance, and membrane transport through the
phosphorylation of a large number of substrates (25, 26). Cdk5
was first implicated in embryonic cortical migration and has
recently been identified as a regulator of postnatal subventricu-
lar zone neuroblast migration (16, 20, 27). Here, we identify
to regulate the survival of adult-generated hippocampal neu-
rons. The migration of new neurons in the hippocampus was not
overtly modified in any of our Cdk5 KO mouse models, which
could be attributed to the requirement of Cdk5 for survival. Our
data demonstrate that hippocampal Cdk5 is essential for survival
of adult-generated neurons, but not for the survival of pre-
existing mature granule neurons or hilar interneurons. Whereas
the survival of cells in vitro may be Cdk5-dependent (28–30), the
neurons. (A) Number of proliferating cells (Ki67?) in WT and Cdk5 cKO mice.
Representative images (B) and quantification (C) of immature neurons in DG
of WT vs. Cdk5 cKO mice via DCX? cell counts (t(9)? 2.2, P ? 0.05; n ? 4 per
group; DCX, red; DAPI blue). (D) Orthogonal image of immunolabeling for
DCX? and Cre reporter YFP? cells. Note DCX? cells exhibit no Cre activity
cells are mature neurons (NeuN?) in Cdk5 cKO mice. (F) Number of dividing
(Ki67?) cells in WT and p35 KO mice. (G) Immunolabeling of DCX? immature
neurons in DG of WT and p35 KO mice with quantification (H, t(6)? 2.9, P ?
0.05; n ? 4 per group). (Scale bars: B and G, 100 ?m; E, 60 ?m.)
Ablation of Cdk5 in Cdk5 cKO mice reduces the number of immature
neurons in AAV-Cre transduced DG (C) and contralateral hemisphere (D). (E) Quantification of DCX? and BrdU? cells (t(8)? 2.2, P ? 0.05; n ? 5 per group).
Viral-mediated ablation of Cdk5 from mature granule cells reduces immature neuron number. Immunolabeling of YFP? cells in YFP reporter fCdk5
Lagace et al. PNAS ?
November 25, 2008 ?
vol. 105 ?
no. 47 ?
present study shows that the in vivo regulation of neuronal
survival by Cdk5 is cell-type specific.
Proliferation and survival of progenitor neurons are likely
important contributors to the composition and function of the
adult hippocampus. Cdk5 appears to predominantly function in
the regulation of pathways involved in the survival of these
neurons. Indeed numerous intrinsic and extrinsic progenitor
survival factors are Cdk5 substrates. For example, DCX and
proto-oncogene B-cell lymphoma protein-2 (Bcl-2) are Cdk5
substrates expressed in immature and mature granule neurons
that might intrinsically mediate neuronal survival (10, 31, 32). In
parallel, altered N-methyl-D-aspartate glutamate receptor
(NMDAR) activity in mature granule neurons may extrinsically
mediate neuronal survival (21, 22) and Cdk5 regulates
NMDAR-mediated excitatory postsynaptic currents (18).
The present study shows Cdk5 is essential for adult neuro-
genesis. In adults, both neurogenesis (33) and Cdk5 (18, 34, 35)
are important in learning and memory. It is also interesting to
note that dysregulation of Cdk5 is implicated in neurodegen-
erative disorders, such as Alzheimer’s disease (25, 26, 36), which
are accompanied by deficiencies in neurogenesis (25, 26, 36).
Thus, it is possible that the cognitive impairments that are
hallmarks of these neurodegenerative diseases may involve both
the loss of existing neurons associated with aberrant Cdk5
activity and the deleterious effects that Cdk5 dysregulation may
impart on hippocampal neurogenesis.
Materials and Methods
Animals. Mice were housed in an Association for Assessment and Accredi-
tation of Laboratory Animal Care International (AAALAC)-approved facil-
ity at UT Southwestern on a 12-h light/dark cycle. The p35 KO (23), p39 KO
(37), nestin-GFP reporter (38), fCdk5 (18, 19), CamKII-Cre(T50)-fCdk5 (31),
and nestin-CreERT2/R26R-YFP (17) mice have been previously described.
Nestin-CreERT2/R26R-YFP mice were crossed with fCdk5 mice to generate
i.p., 5 days) and killed at 12 or 30 days post-TAM. Mice were genotyped as
Dentate-Specific Cdk5 KO via AAV. Serotype 2-rAAV-Cre was generated as
previously described (19) and unilaterally delivered to the DG of adult ho-
mozygous fCdk5 or WT littermates (10–12 weeks old, coordinates from
bregma at skull surface AP-1.7, LM ? 1.2, DV-2.4, 1 ?l per injection). Mice
on a freezing microtome. Slides underwent antigen retrieval (0.01 M citric
acid, pH 6.0, 100°C for 15 min) and BrdU-labeled sections underwent mem-
brane permeabilization (0.1% trypsin in 0.1 M Tris and 0.1% CaCl2, 10 min),
and DNA denaturation (2 N HCl in 1? PBS, 30 min). To remove endogenous
peroxidase activity, sections were incubated with 0.3% H2O2 for 30 min.
Nonspecific binding was blocked with 3% donkey serum (Jackson Immuno-
Laboratories) and 0.3% Triton-X in PBS for 30–60 min. Primary Abs included
rat anti-BrdU (1:500, Accurate), rabbit AC3 (1:500, Cell Signaling), goat anti-
detection; 1:500, Invitrogen), and rabbit anti-Ki67 (1:500, Vector Laborato-
purified protein at the UT Southwestern Ab Core facility (Fig. S1). For double
labeling, primary Abs were simultaneously incubated (AC3/YFP, BrdU/YFP,
Cdk5/YFP, DCX/YFP; Ki67/YFP) and processed for each Ab separately. For AC3,
BrdU, and NeuN, a fluorescent-tagged secondary Ab (1:200, Jackson Immu-
noResearch) was used. For Cdk5, DCX, Ki67 or YFP, a biotin-tagged secondary
Ab (1:200, Jackson ImmunoResearch) was followed by ABC (Vector Laborato-
ries) and Tyramide-Plus signal amplification (1:50, PerkinElmer). Slides were
performed as previously described (19).
Quantification of immunoreactive hippocampal cells was performed with
an Olympus BX-51 microscope (400?) as previously described and validated
(41). Briefly, an observer blind to experimental groups counted YFP? cells via
stereology and use of the optical fractionation method through analysis of
from bregma). For viral-transduced tissue, YFP? cells were counted in both
hemispheres in 3 sections within the injection penumbra with blinding for
injection side and genotype. Phenotypic analysis and classification of YFP?
cells (?50–150 cells per mouse, n ? 4–6 mice per time point) was performed
by using a confocal microscope (Leica TCS SL confocal and Zeiss Axiovert 200
and LSM510-META; emission wavelengths 488, 543, and 633, 630? and
imported into the 3D Velocity (Improvision) reconstruction program for 3-D
Statistical Analyses. Data are reported as mean ? SEM. Experiments with two
were performed by using ANOVA followed by a Bonferroni post hoc test.
Statistical significance was defined as P ? 0.05.
Masahiro Yamaguchi for the nestin-GFP reporter mice; Pierre Chambon for
chio for providing pure Cdk5 for the generation of antibody; and Eric Nestler
for assistance with this study; and Laure Farnbauch, David Pyle, Stephanie
Rogan, Greg Wallingford, Sumana Chakravarty, and Ezekiell Mouzon for
technical assistance. This work was supported by a postdoctoral fellowship
from the Canadian Institute of Health Research (to D.C.L.); National Institutes
of Health Grants DA10044 and MH074866 (to P.G.), DA16672 and MH079710
(to J.A.B.), and R01 DA016765, R21 DA023701, and K02 DA023555 (to A.J.E.);
and Cure Alzheimer’s Fund (P.G.).
1. Cameron HA, Woolley CS, McEwen BS, Gould E (1993) Differentiation of newly born
neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56:337–344.
2. Kempermann G, Gast D, Kronenberg G, Yamaguchi M, Gage FH (2003) Early determi-
of mice. Development 130:391–399.
adult brain. Curr Opin Neurobiol 18:108–115.
4. Zhang CL, Zou Y, He W, Gage FH, Evans RM (2008) A role for adult TLX-positive neural
stem cells in learning and behavior. Nature 451:1004–1007.
5. Ueki T, et al. (2003) A novel secretory factor, Neurogenesin-1, provides neurogenic
environmental cues for neural stem cells in the adult hippocampus. J Neurosci
6. Hellmich MR, Pant HC, Wada E, Battey JF (1992) Neuronal cdc2-like kinase: A cdc2-
related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci
proline-directed protein kinase from bovine brain. J Biol Chem 267:13383–13390.
8. Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E (1994) p35 is a neural-specific
regulatory subunit of cyclin-dependent kinase 5. Nature 371:419–423.
with p35. Mol Cell Biol 23:5090–5106.
10. Tanaka T, Serneo FF, Tseng HC, Kulkarni AB, Tsai LH, Gleeson JG (2004) Cdk5 phos-
11. Rao MS, Shetty AK (2004) Efficacy of doublecortin as a marker to analyze the absolute
number and dendritic growth of newly generated neurons in the adult dentate gyrus.
Eur J Neurosci 19:234–246.
12. Zheng M, Leung CL, Liem RK (1998) Region-specific expression of cyclin-dependent
kinase 5 (cdk5) and its activators, p35 and p39, in the developing and adult rat central
nervous system. J Neurobiol 35:141–159.
13. Delalle I, Bhide PG, Caviness VS Jr, Tsai LH (1997) Temporal and spatial patterns of
expression of p35, a regulatory subunit of cyclin-dependent kinase 5, in the nervous
system of the mouse. J Neurocytol 26, 283–296.
and Cdk5 kinase activity in developing, adult, and aged rat brains. Neurochem Res
15. Plumpe T, et al. (2006) Variability of doublecortin-associated dendrite maturation in
adult hippocampal neurogenesis is independent of the regulation of precursor cell
proliferation. BMC Neurosci 7:77.
16. Ohshima T, et al. (1996) Targeted disruption of the cyclin-dependent kinase 5 gene
results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl
Acad Sci USA 93:11173–11178.
17. Lagace DC, et al. (2007) Dynamic contribution of nestin-expressing stem cells to adult
neurogenesis. J Neurosci 27:12623–12629.
18. Hawasli AH, et al. (2007) Cyclin-dependent kinase 5 governs learning and synaptic
plasticity via control of NMDAR degradation. Nat Neurosci 10:880–886.
19. Benavides DR, et al. (2007) Cdk5 modulates cocaine reward, motivation, and striatal
neuron excitability. J Neurosci 27:12967–12976.
www.pnas.org?cgi?doi?10.1073?pnas.0810137105 Lagace et al.
20. Hirota Y, et al. (2007) Cyclin-dependent kinase 5 is required for control of neuroblast Download full-text
migration in the postnatal subventricular zone. J Neurosci 27:12829–12838.
21. Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH (2006) NMDA-receptor-mediated,
cell-specific integration of new neurons in adult dentate gyrus. Nature 442:929–
22. Ge S, Yang CH, Hsu KS, Ming GL, Song H (2007) A critical period for enhanced synaptic
plasticity in newly generated neurons of the adult brain. Neuron 54:559–566.
23. Chae T, Kwon YT, Bronson R, Dikkes P, Li E, Tsai LH (1997) Mice lacking p35, a neuronal
specific activator of Cdk5, display cortical lamination defects, seizures, and adult
lethality. Neuron 18:29–42.
24. Hayes NL, Nowakowski RS (2002) Dynamics of cell proliferation in the adult dentate
gyrus of two inbred strains of mice. Brain Res Dev Brain Res 134:77–85.
25. Dhavan R, Tsai LH (2001) A decade of CDK5. Mol Cell Biol 2:749–759.
26. Cruz JC, Tsai LH (2004) A Jekyll and Hyde kinase: Roles for Cdk5 in brain development
and disease. Curr Opin Neurobiol 14:390–394.
27. Hirasawa M, et al. (2004) Perinatal abrogation of Cdk5 expression in brain results in
neuronal migration defects. Proc Natl Acad Sci USA 101:6249–6254.
28. Cheung ZH, Ip NY (2004) Cdk5: Mediator of neuronal death and survival. Neurosci Lett
through phosphorylation of Bcl-2. J Neurosci 28:4872–4877.
30. O’Hare MJ, et al. (2005) Differential roles of nuclear and cytoplasmic cyclin-
dependent kinase 5 in apoptotic and excitotoxic neuronal death. J Neurosci
31. Kuhn HG, Biebl M, Wilhelm D, Li M, Friedlander RM, Winkler J (2005) Increased
ing continued hippocampal neurogenesis. Eur J Neurosci 22:1907–1915.
32. Friocourt G, Liu JS, Antypa M, Rakic S, Walsh CA, Parnavelas JG (2007) Both doublecor-
tin and doublecortin-like kinase play a role in cortical interneuron migration. J Neu-
33. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult
neurogenesis. Cell 132:645–660.
fear conditioning by baseline and inducible septo-hippocampal cyclin-dependent
kinase 5. Neuropharmacology 44:1089–1099.
35. Sananbenesi F, et al. (2007) A hippocampal Cdk5 pathway regulates extinction of
contextual fear. Nat Neurosci 10:1012–1019.
36. Abdipranoto A, Wu S, Stayte S, Vissel B (2008) The role of neurogenesis in neurode-
generative diseases and its implications for therapeutic development. CNS Neurol
Disord Drug Targets 7:187–210.
37. Ko J, et al. (2001) p35 and p39 are essential for cyclin-dependent kinase 5 function
during neurodevelopment. J Neurosci 21:6758–6771.
38. Yamaguchi M, Saito H, Suzuki M, Mori K (2000) Visualization of neurogenesis in the
central nervous system using nestin promoter-GFP transgenic mice. Neuroreport
39. Indra AK, et al. (1999) Temporally-controlled site-specific mutagenesis in the basal
layer of the epidermis: Comparison of the recombinase activity of the tamoxifen-
inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res 27:4324–4327.
40. Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat
41. Mandyam CD, Harburg GC, Eisch AJ (2007) Determination of key aspects of precursor
cell proliferation, cell cycle length and kinetics in the adult mouse subgranular zone.
Lagace et al. PNAS ?
November 25, 2008 ?
vol. 105 ?
no. 47 ?