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History of postnatal neurogenesis discovery http://www.nature.com/nrn/journal/v1/n1/pdf/nrn1000_067a.pdf
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Neural Stem Cell Biology
Postnatal neurogenesis discovery Neural stem cell discovery
Embryonic NSCs Adult NSCs BCH/GGB512 Richard Gronostajski History
of postnatal neurogenesis discovery
History of postnatal neurogenesis discovery
1800s-1950s no way of measuring proliferation other than mitosis
Saw occasional mitoses but couldn't tell if they were neurons 1950s
H3 thymidine first used in vivo 1961 3H TdR first applied to adult
brain (I. Smart) saw new neurons in 3 day old mice, not adults 1960
(Joseph Altman) 3H TdR adult rats, saw labeling in cortex,
hippocampus, olfactory bulb. Ignored for almost 40 years (bias
against Altman, he got the last word, didn't get tenure at MIT, did
at Purdue) History of postnatal neurogenesis discovery
Injected P20+21, harvested P60 History of postnatal neurogenesis
discovery
1960 (Joseph Altman) 3H TdR adult rats, saw labeling in cortex,
hippocampus, olfactory bulb. Ignored for almost 40 years 1977
Michael Kaplan's EM studies confirmed neurogenesis. Pasko Rakic's
papers found "little or no" adult neurogenesis. 1988 Stanfield and
Trice showed adult neurogenesis with fluorescent tracer + 3H TdR
Fred Gage and coworkers used BrdU and cell-type markers 1999 Rakic
showed neurogenesis with BrdU incorporation and cell-type specific
markers. Postnatal neurogenesis
FIG. 2. Newly generated cells in the adult macaque dentate gyrus
express neuronal phenotypic markers 32 days after five BrdU
injections, as detected by immunofluorescence double-label and
confocal microscopy. (ad) Neurons in the dentate gyrus express NeuN
(red). The same cell in the GCL that is labeled with BrdU (arrow,
green in b) also expresses NeuN (arrow, a). (c and d) An example of
a BrdU-labeled nucleus (d, arrow, green) that did not emit a red
fluorescence signal (c, arrow), demonstrating that the BrdU
fluorescent signal did not bleed into the red channel; this might
be a progenitor or new glial cell. (e and f ) A TuJ1-positive cell
in the SGZ (arrow, red) colabels with BrdU in its nucleus ( f,
arrow, green). Note the slender process (arrowheads) emanating from
the cell body, resembling the trailing process of a newly generated
migrating neuron. The BrdU in its nucleus confirms its recent
generation. (g and h) Two cells in the SGZ expressing TuJ1 in the
cytoplasm surrounding their nuclei (red), which are immunopositive
for BrdU (h, green). Their close proximity suggests that these two
cells might be newly generated siblings. The long thin process
(arrowheads), consistent with migratory behavior, is clearly seen
in one of the cells. (i and j) A bipolar cell in the SGZ
coexpressing TuJ1 (green) and nuclear BrdU (j, orange). Although
most double-labeled cells were oriented radially in the GCL,
occasionally a cell was oriented parallel to the GCL. This example
shows such a BrdU-labeled cell with an extended process on either
side of the nucleus. (k) A TuJ1-positive cell (green, arrow) with a
BrdU-positive nucleus (orange) has an immature migratory
appearance. Note the thin trailing process (arrowheads) and a
nearby BrdU-negative neuron, with a mature, apical process
(arrowcross). (l) A cell deep in the GCL colabels with TuJ1 (green)
and BrdU (orange) with an apical process that is thick and
tortuous, similar to the dynamic, exploratory leading process of a
migrating neuron (its trailing process is out of the optical
plane). Compare this with the straighter apical process of the more
mature BrdU-immunonegative granule neuron in k (arrowcross). [Bar
(al) 5 10 mm.] Neurobiology: Kornack and Rakic Proc. Natl. Acad.
Sci. USA 96 (1999) 5771 Major reasons for 40 year delay
Lack of good markers for both proliferation and cell types. Bias
against the idea. Neural Stem Cells in vitro Neural Stem Cells in
vitro
Fig. 1. EGF-induced proliferation of cells isolated from the adult
mouse striatum. (A) After 2 DIV, cells that hadundergone cell
division were first observed. Cell division continued at 3(B) and
4-(C) DIV, although dividing cells beginning to form a cluster
migrated slowly across the substrate. (D) After 6 to 8DIV, spheres
of cells lifted off the substrate and floated insuspension. Line in
substrate (A through C) serves toidentify the field. (E) One hour
after plating onto poly-L-ornithine, a 6 DIV sphere attached to the
substrate. (F) The cells in(E) were immunostained with antibody to
nestin; virtually all cells wereimmunoreactive for nestin. Self
renewal shown (G through J) Single cells, derived from dissociated
6- to 8-DIV spheres,were plated in single wells of a 96-well plate;
A large, hypertrophic cellafter 2DIV (G) began todivide and form
cluster of cells during the subsequent 3 (H), 4 (I), and 6 (J) DIV.
Scratches insubstrate serve to den tify the field. Scale bars:(A
through D) bar in(D) denotes 50um (E), 50 um;(F), 25 um;(G through
J)bar in (J), 50 um. Neurospheres Neural Stem Cells in vitro
FIG. 1. Morphology of neurons generated by culturing adult brain
cells with bFGF and then with medium conditioned by Ast-1 cells.
Neurons stained by immuno-fluorescence for expression of 150-kDa
neurofilament (b, d, f, and h)have various morphologies and, as
shown by phase-contrast micrography, their nuclei are labeled with
[3H]thymidine (arrowsin a, c, e, and g).The silver grains are more
easily seen in g, where the plain of focus is at the emulsion
level. (a-f x280;g and h X450.) Neural Stem Cells in vitro
Neurosphere assay Primary neurospheres may measure stem and
progenitor cells.Initial passage Secondary neurospheres may measure
stem cells.Second passage. Assay controversial, spheres and split
or merge, best to make at limiting dilution. Question everything
you read!
Lack of good markers for both proliferation and cell types. Bias
against an idea doesn't mean it isn't true. Summary of embryonic
and adult neurogenesis
Protoplasmic or fibrous astrocytes DCX+ Nestin- GFAP- GLAST+
Nestin+ GFAP+ Pax6+ Tbr2+ Figure 1 | Patterns of gliogenesis in
embryonic and adult progenitor zones. The progression from the
embryo to the adult is shown from left to right (a to c). Black
arrows indicate self-renewal or differentiation from one cell type
to another. Markers of macroglia and their precursors are listed.
a, Self-renewing neuroepithelial cells line the ventricles
throughout the neuraxis at the stages of neural tube closure. These
cells may generate some neurons. Neuroepithelial cells are
transformed into radial glial cells as neurogenesis begins. b,
Radial glia produce intermediate progenitor cells and
oligodendrocyte precursor cells (OPCs), which in turn produce
neurons and oligodendrocytes, respectively. Radial glia can also
become astrocytes, as well as producing intermediate progenitors
that expand in number before producing astrocytes. Protoplasmic
astrocytes and fibrous astrocytes might arise from common or
independent progenitors. Radial glia also produce ependymal cells.
c, In adults, oligodendrocytes are produced by two independent
pathways: type B cells in the cortical subventricular zone produce
transit-amplifying cells (known as type C cells), which in turn
produce OPCs as well as neurons. The OPCs subsequently generate
oligodendrocytes, and OPCs that are already resident in the grey
matter also produce oligodendrocytes. ALDH1L1, aldehyde
dehydrogenase 1 family, member L1; APC, adenomatous polyposis coli;
GFAP, glial fibrillary acidic protein; MBP, myelin basic protein;
PDGFR-, platelet-derived growth factor receptor-; PLP, proteolipid
protein 1. All green cells are intermediate progenitors, with type
C cells being a subset of these, and all blue cells are neural stem
cells (even though each blue cell is a different type). Subgranular
zone hippocampus Nestin+, GFAP+ Pax6+ Blue cells - stem cellsGreen
cells - intermediate progenitor cells Orange cells neuronal
progenitors and neurons Modified from: Developmental genetics of
vertebrate glial-cell specification.Rowitch DH, Kriegstein AR.
Nature Nov 11;468(7321):214-22 Evidence GFAP-GFP transgene
expression
Fig. 1. Green fluorescent radial glial cells of 94-4 transgenic
mice, in which the human GFAP-promoter drives expression of the
S65Tmutant green fluorescent protein (GFP) (Zhuo et al., 1997). (A)
GFP-immunostained and (B) GLAST-immunoreactive radial glial cells
in frontal sections from E16 (A) and E14 (B) mouse cortex (pial
surface upwards in A and towards the upper right corner in B). (C)
depicts GFP-immunostained cells from acutely dissociated E14 cortex
double stained with GLAST antiserum (D). Filled arrowheads depict
double-positive cells and open arrowheads double-negative cells in
the corresponding fluorescent micrographs. This shows that GFP is
localized in GLAST-containing precursor cells with radial glial
morphology. Scale bars: 25 mm. GFAP-GFP transgene is expressed in
GLAST+ cells that form radial pattern Sorted GFP+ and put in
culture
Fig. 2. Characterization of green fluorescent cells isolated from
the cortex of hGFAP-GFP transgenic mice and their progeny. Green
fluorescent cells were isolated from the transgenic mouse line 94-4
expressing GFP under the control of the human GFAP promoter (Zhuo
et al., 1997; Fig. 1). (A-C) depict examples of sort profiles of
cells from E14 (A), E16 (B) and E18 (C) cortex. The left columns in
(A-C) show the dot plots of cells in forward scatter (FSC) and side
scatter (SSC) with a polygon indicating the gate selecting the
healthy cells. The histograms in the right columns in (A-C) show
the number of cells (events, y-axis) with a fluorescent intensity
indicated on the x-axis of wild-type controls (upper panels) and
hGFAP-GFP transgenic littermates (lower panels). The percentage of
fluorescent cells in the sort gate (grey shading, A-C) is
indicated. (A-C) depict the composition of cells 2 hours (2h) or
5-7 days after the sort (days in vitro, div). A few cells sorted
from mouse cortex were plated on a rat cortex feeder layer and
identified by their M2M6 immunoreactivity, as depicted in Fig. 3.
Clusters of M2M6-positive cells after 2 hours were mostly (97%)
single cells and were double stained with antiserum directed
against b-tubulin-III as a neuronal and RC2, GLAST, BLBP, Ki67 or
nestin as precursor markers. Neurons are depicted in blue,
precursor cells in green, indicating their differential RC2,
RC2/GLAST, RC2/GLAST/BLBP or GLAST/BLBP immunoreactivity as
depicted in the figure. Note that almost all sorted precursor cells
are GLAST immunoreactive. Clusters after 7 div contained, in most
cases, several cells and were interpreted as clones derived from
single plated precursor cells. Clusters were classified as pure
neuronal when all cells of a cluster were b-tubulin-III
immunoreactive (see example in Fig. 3E,F) and their proportion is
depicted in blue, as pure non-neuronal when no cell of a clone was
b-tubulin-III immunoreactive (depicted in red), but cells were
nestin or GFAP positive (see examples in Fig. 3G-J) and as mixed
neuronal and non-neuronal when clones contained b-tubulin-
III-positive and -negative cells (depicted in orange). Note the
large increase in the number of neuronal clusters at E14 and E16
(A,B), suggesting that most GLAST-positive precursors generate
neurons at this stage. In contrast, the progeny were mostly
astrocytes when cells were isolated from an E18 cortex (C).
GFAP-GFP+ cells made neurons, glia and mixed colonies when put into
culture of 5-7 days.Some contaminating neurons present in starting
material Types of colonies made in vitro
Filled arrowheads indicate double-labeled cells, open arrowheads
indicate single-labeled cells in corresponding micrographs. Note
that GLAST-positive precursor cells generate neurons and astrocytes
in two separate lineages. Scale bars: 25um. Fig. 3. Examples of the
progeny of hGFAP-GFP- and GLASTpositive precursor cells isolated by
fluorescence-activated cell sorting. Cells were sorted from E14
(A-H) and E18 (I,J) mouse cortex by green fluorescent protein
content driven from the human GFAP promoter (Zhuo et al., 1997; see
Fig.1, sort gates as in Fig. 2). The sorted cells were cultured for
5-7 days. In C-J, sorted cells were cultured on a rat cortex feeder
layer of the corresponding age and identified by the mouse-specific
antibody M2M6 (Lagenaur and Schachner, 1981; Lund et al., 1985)
(C,E,G,I). Clusters of labeled cells were considered as clones
derived from a single sorted precursor cell, as illustrated in the
overview in C,D. Cell-typespecific antibodies were used as
indicated in the panels to identify the composition of the clones.
Pure neuronal clones were composed exclusively of
b-tubulin-III-positive cells extending neurites marked by arrows
(E,F). Neurons were generated in vitro and incorporated BrdU (red
in B). An example of a non-neuronal clone generated from E14
precursors containing a GFAP-positive cell (filled arrowhead) is
depicted in G,H. (I,J) A non-neuronal clone composed exclusively of
GFAP-positive astrocytes generated by cells sorted from E18 cortex.
Filled arrowheads indicate double-labeled cells, open arrowheads
indicate single-labeled cells in corresponding micrographs. Note
that GLAST-positive precursor cells generate neurons and astrocytes
in two separate lineages. Scale bars: 25mm. Fig. 3. Examples of the
progeny of hGFAP-GFP- and GLAST positive precursor cells isolated
by fluorescence-activated cell sorting. Cells were sorted from E14
(A-H) and E18 (I,J) mouse cortex by green fluorescent protein
content driven from the human GFAP promoter. The sorted cells were
cultured for 5-7 days. In C-J, sorted cells were cultured on a rat
cortex feeder layer of the corresponding age and identified by the
mouse-specific antibody M2M6 (Lagenaur and Schachner, 1981; Lund et
al., 1985) (C,E,G,I). Clusters of labeled cells were considered as
clones derived from a single sorted precursor cell, as illustrated
in the overview in C,D. Cell-type specific antibodies were used as
indicated in the panels to identify the composition of the clones.
Pure neuronal clones were composed exclusively of
b-tubulin-III-positive cells extending neurites marked by arrows
(E,F). Neurons were generated in vitro and incorporated BrdU (red
in B). An example of a non-neuronal clone generated from E14
precursors containing a GFAP-positive cell (filled arrowhead) is
depicted in G,H. (I,J) A non-neuronal clone composed exclusively of
GFAP-positive astrocytes generated by cells sorted from E18 cortex.
Patterns of embryonic neurogenesis
Neural tube E11-12 Neural tube E11-12 ~E14-E15 ~E14-E15 Figure 2 |
Patterning of the neural tube generates unique domains for neuronal
and glial progenitors. a, The primitive neuroepithelium of the
neural tube is patterned by organizing signals. These signals
emanate from the ventral floor plate (such as SHH, purple) and roof
plate (BMPs and WNTs, green). b, A cross-sectional view of the
neural tube is shown. Progenitors of motor neurons and interneurons
are formed within distinct regionally restricted domains of the
ventral neural tube: the p0, p1, p2 and p3 domains for interneuron
subtypes, and the pMN domain for motor neurons. Dorsal domains are
also similarly parcelled (not shown). Signalling mediated by SHH
(gradient denoted by purple circles) regulates the expression of
transcription factors (for example, NKX2.2, OLIG2, PAX6 and SCL) in
the ventral neural tube. The interactions of these factors sharpen
and maintain the domain boundaries. Embryonic OPCs are derived
mainly from the pMN domain. OPCs are recognized by expression of
PDGFR-, SOX10 and NG2. Three astrocyte subtypes have been
identified: VA1 astrocytes (which express PAX6 and reelin, derived
from p1) are the most dorsal; VA3 astrocytes (which express NKX6.1
and SLIT1, derived from p3) are the most ventral; and VA2
astrocytes (which express PAX6, NKX6.1, reelin and SLIT1, derived
from p2) are located in an intermediate white-matter domain. c,
Organizing centres of the forebrain are shown. These include the
cortical hem (purple), which is a dorsal source of BMPs and WNTs; a
ventral centre (green), which is a source of SHH; and rostral
(pink) and anti-hem (blue) regions, which are sources of growth
factors such as FGF8, and transforming growth factor- (TGF-) and
FGF7, respectively. d, A coronal view of the embryonic (~E14.5)
forebrain showing its division into dorsal and ventral regions that
are specialized for producing different neuron and glial-cell
types. The dorsal region includes the cortex, a source of pyramidal
neurons and astrocytes. The ventral region includes the lateral and
medial ganglionic eminences and the pre-optic area, which are
sources of GABA (-aminobutyric acid)-containing interneurons and
oligodendrocytes. The green, blue and red shaded areas represent
the pre-optic area, medial/lateral ganglionic eminences and
neocortex, respectively (see Fig. 3). Transcription factors that
are associated with dorsal (NGN1, NGN2, GLI3) and ventral (ASCL1,
DLX1, DLX2) patterning and cell fate specification are indicated.
NGN, neurogenin. Multiple types of embryonic neural
progenitors
Similar to what you saw in the retina lecture, Interkinetic nuclear
migration Neural progenitor cell not Neural Stem cell Symmetric vs.
Asymmetric cell divisions! Several types of progenitors contribute
to neurogenesis in the mammalian cortex [1214]. (a) At the
beginning of neurogenesis (around E11E12 in the mouse),
neuroepithelial cells located in the ventricular zone (VZ) and
undergoing interkinetic nuclear migration either divide
symmetrically to generate two new neuroepithelial cells or divide
asymmetrically to generate either a neuroepithelial cell and a
neuron, which migrates to the preplate (PP), or a neuroepithelial
cell and a basal progenitor, which divides symmetrically on the
basal side of the VZ (bVZ) to generate two neurons. (b) As
neurogenesis progresses (around E13E17 in the mouse), several
signalling pathways induce the expression of glial markers by
neuroepithelial cells, which thus become radial glial cells. These
cells also divide either symmetrically, to generate two radial
glial cells, or asymmetrically, to generate a radial glial cell and
either a neuron, which migrates through the intermediate zone (IZ)
into the cortical plate (CP), or a basal progenitor, which moves to
the subventricular zone (SVZ) and divides symmetrically to generate
two neurons. MZ, marginal zone. Neural progenitor cell not Neural
Stem cell Niches of adult neurogenesis
Newly generated NSCs TACs Fig. 1. Adult neurogenesis occurs
primarily in the subventricular zone (SVZ) and subgranular zone
(SGZ). In this sagittal view of the adult mouse brain, the
neurogenic regions are indicated in blue. In the SVZ, stem cells
(green) reside in the wall of the lateral ventricle, just below the
ependymal layer (gray), and give rise to transit amplifying cells
(light blue) and neuroblasts (purple). These neuroblasts migrate in
chains in the rostral migratory stream (RMS) to reach the olfactory
bulb (OB), where they mature into functionally integrated granule
(peach) and periglomerular (red) neurons. In the SGZ of the
hippocampal dentate gyrus (DG), stem cells (green) clustered near
the base of the hippocampal DG granule cell layer (GCL) give rise
to transit amplifying progenitors (light blue). These give rise to
neuroblasts (blue), newborn neurons (purple), and eventually to
immature (magenta) and mature (peach) granule cell neurons that
primarily exist in the inner or hilar half of the GCL but extend
their processes out to the molecular layer to receive cortical
input. Note that SVZ neuroblasts migrate a relatively long distance
to the OB to give rise to mature neurons, while SGZ progenitors
move barely into the GCL to give rise to ma- ture neurons. NSCs
TACs NBs Derived from VZ of cortex SVZ = Subventricular Zone, RMS =
Rostral Migratory Stream, SGZ = Subgranular Zone of Dentate Gyrus
OB = Olfactory bulb, NSC = neural stem cell, TAC = transient
amplifying cells (progenitors), NB = neuroblast Modified from:
Madeleine A. Johnson, Jessica L. Ables & Amelia J.
EischCell-intrinsic signals that regulate adult neurogenesis.BMB
Reports 2010 Mouse hippocampus development
FIGURE 1| Development of the mouse hippocampus. Schematic
representation of the dorsal telencephalon at different embryonic
(E )stages and at birth (P0). The indicated area in each picture
corresponds to the hippocampal region and is magnified on its right
hand side (bluesquares). (A) At E12.5 the presumptive DNE (dentate
neuroepithelium) is located between the HNE (hippocampal
meuroepithelium) and the CH (cortical hem), which produces
Cajal-Retzius cells (orange), shown lining the pial side of the
cortex. (B) At E14.5 dentate precursors of the primary matrix (dark
blue circles) are located in the VZ, and precursor cells start to
migrate towards the pial side of the cortex forming the secondary
matrix. In the VZ of the HNE, radial glial precursors (depicted in
dark blue and triangular body shape) will give rise to hippocampal
neurons. (C) At E17.5 the hippocampal fissure is formed and dentate
precursor cells migrate to and accumulate there, forming the
tertiary matrix (light blue).Cajal-Retzius cells are also present
and follow the hippocampal fissure. At this stage the glial
scaffold (not shown) extends from the CH to the hippocampal fissure
and pial surface, directing the migration of dentate precursor
cells. From the HNE, hippocampal neurons (red triangles) are born
and migrate along radial glial cells towards their location in the
hippocampal fields (CA1 and CA3 are shown). (D) At birth the blades
of the DG (dentate gyrus) start to form. Granule neurons in the DG
(red triangles) appear first in the upper blade, below the
hippocampal fissure. The continuous migration of Cajal-Retzius
cells reaches the pial side and promotes the formation of the lower
blade of the DG. Precursor cells in the primary and secondary
matrix will soon disappear, but cells in the tertiary matrix
continue actively dividing and producing granule neurons through
postnatal DG development. HNE, hippocampal neuroepithelium; DNE,
dentate neuroepithelium; CH, cortical hem; VZ, ventricular zone;
1ry, primary matrix; 2ry, secondary matrix;3ry, tertiary matrix;
DG, dentate gyrus; D, dorsal; M, medial; V, ventral; L, lateral.
HNE, hippocampal neuroepithelium DNE, dentate neuroepithelium CH,
cortical hem VZ, ventricular zone 1ry, primary matrix 2ry,
secondary matrix 3ry, tertiary matrix DG, dentate gyru D, dorsal;
M, medial; V, ventral; L, lateral. Some differences between
embryonic and adult neurogenesis Birthdating of progenitors
Inject retrovirus on specific day with GFP or other label (only
labels dividing cells) Follow fate of labeled cells over time Can
also use tamoxifen and Cre-ERT2 and a flox-stopped FP Can also use
BrdU or EdU to label cell division. Can follow over days, weeks,
months and then stain for "Birthdating marker" Adult neurogenesis
Adult neurogenesis SVZ to OB Dentate Gyrus of hippocampus Summary
of embryonic and adult neurogenesis
Protoplasmic or fibrous astrocytes DCX+ Nestin- GFAP- GLAST+
Nestin+ GFAP+ Pax6+ Tbr2+ Figure 1 | Patterns of gliogenesis in
embryonic and adult progenitor zones. The progression from the
embryo to the adult is shown from left to right (a to c). Black
arrows indicate self-renewal or differentiation from one cell type
to another. Markers of macroglia and their precursors are listed.
a, Self-renewing neuroepithelial cells line the ventricles
throughout the neuraxis at the stages of neural tube closure. These
cells may generate some neurons. Neuroepithelial cells are
transformed into radial glial cells as neurogenesis begins. b,
Radial glia produce intermediate progenitor cells and
oligodendrocyte precursor cells (OPCs), which in turn produce
neurons and oligodendrocytes, respectively. Radial glia can also
become astrocytes, as well as producing intermediate progenitors
that expand in number before producing astrocytes. Protoplasmic
astrocytes and fibrous astrocytes might arise from common or
independent progenitors. Radial glia also produce ependymal cells.
c, In adults, oligodendrocytes are produced by two independent
pathways: type B cells in the cortical subventricular zone produce
transit-amplifying cells (known as type C cells), which in turn
produce OPCs as well as neurons. The OPCs subsequently generate
oligodendrocytes, and OPCs that are already resident in the grey
matter also produce oligodendrocytes. ALDH1L1, aldehyde
dehydrogenase 1 family, member L1; APC, adenomatous polyposis coli;
GFAP, glial fibrillary acidic protein; MBP, myelin basic protein;
PDGFR-, platelet-derived growth factor receptor-; PLP, proteolipid
protein 1. All green cells are intermediate progenitors, with type
C cells being a subset of these, and all blue cells are neural stem
cells (even though each blue cell is a different type). Subgranular
zone hippocampus Nestin+, GFAP+ Pax6+ Blue cells - stem cellsGreen
cells - intermediate progenitor cells Orange cells neuronal
progenitors and neurons Modified from: Developmental genetics of
vertebrate glial-cell specification.Rowitch DH, Kriegstein AR.
Nature Nov 11;468(7321):214-22 Summary and ongoing questions
Symmetric vs. Asymmetric cell divisions Quiescence vs.
proliferation Types of NSCs, SVZ vs. SGZ and others Regulation by
Niche Regulation by hormones Regulation by exercise How do they
mediate memory Why is there a decrease with aging Will they be
useful for therapies For Thursday Read paper Do Figure Facts
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