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Science 4 April 1997:
Vol. = 276. no.=20 5309, pp. 66 - 71
DOI: = 10.1126/science.276.5309.66

Prev= =20 | Tab= le=20 of Contents | Next= =20

Articles

Stem Cells in the Central Nervous System=20

Ronald McKay=20
In the vertebrate central nervous system, multipotential cells = have=20 been identified in vitro and in vivo. Defined mitogens⁼cause=20 the proliferation of multipotential cells in vitro, the⁼²⁰magnitude of which is sufficient to account for the number = of⁼²⁰cells in the brain. Factors that control the differentiation = of⁼²⁰fetal stem cells to neurons and glia have been defined in=20 vitro,and multipotential cells with similar signaling = logic=20 can be culturedfrom the adult central nervous system.=20 Transplanting cells tonew sites emphasizes that=20 neuroepithelial cells have the potentialto integrate = into many=20 brain regions. These results focus attentionon how = information=20 in external stimuli is translated into thenumber and = types of=20 differentiated cells in the brain. The developmentof = therapies=20 for the reconstruction of the diseased or injuredbrain = will be=20 guided by our understanding of the origin and stability⁼of cell=20 type in the central nervous system.

The author is in the = Laboratory of=20 Molecular Biology, National Institute of Neurological Disorders = and=20 Stroke, Bethesda, MD 20892, USA.

Definition of the processes that shape the cellular makeup of the = central=20 nervous system (CNS) has relied heavily on three⁼distinct=20 procedures: fate mapping, tissue culture, and = transplantation.⁼²⁰These traditional tools of embryologists have been=20 significantlyimproved by the recent incorporation of = advanced=20 molecular methods.Fate mapping of neuronal precursors = in=20 vertebrates points to theexistence of multipotential = cells=20 that are precursors to bothneurons and glia (1).=20 However, this approach does not necessarilyreveal the = full=20 proliferation and differentiation capability ofthe = cells. In=20 vitro and in vivo manipulations must be used totest = the=20 developmental potential of a cell. Tissue culture and⁼²⁰transplant techniques, developed in vertebrate systems (2),⁼²⁰have generated important data on the potential of neural = cells⁼²⁰(3).=20
Defining a Stem Cell
To be considered a stem cell in the = CNS, a=20 cell must have the potential to differentiate into neurons, = astrocytes,=20 and oligodendrocytesand to self-renew sufficiently to = provide=20 the numbers of cellsin the brain. The term = "progenitor" refers=20 to a cell with a morerestricted potential than a stem = cell.=20 "Precursor" is a less stringentterm that refers to any = cell=20 that is earlier in a developmentalpathway than = another.=20
The complete cellular lineage of the nematode Caenorhabditis = elegans has been described (4)=20 and is an influential instanceof the power of = morphological=20 analysis to define precursor-productrelations in vivo. = However, in the CNS of mammals, there are toomany = cells for=20 each to be followed individually. The problem is⁼similar to the=20 technical difficulties biochemists faced in defining⁼metabolic=20 pathways. Without access to pure precursor, it was difficult⁼to=20 establish the catalytic step actually performed by a given⁼²⁰enzyme. When this hurdle was overcome, it was recognized = that⁼²⁰enzymes perform discrete chemical steps, ultimately giving = rise⁼²⁰to the important concept of one gene-one enzyme (5).=20 Similarly,to understand the developing brain, we need = to=20 purify the precursorcell types and define their = transitions=20 into differentiated progeny.Early work revealed that = fetal=20 cells removed from the developingbrain and placed in = vitro=20 could give rise to differentiated neurons(6).=20 For the most part, these neurons were derived from cells⁼that=20 did not divide in tissue culture, although cells that did⁼²⁰divide could acquire some features of immature neurons (7).⁼²⁰

The intermediate filament nestin is a major cytoskeletal = protein in=20 neuronal precursors in the mammalian CNS (8).=20 Nestinis first detected at the earliest steps in = neural plate=20 induction(9),=20 and most cells in the neuroepithelium are nestin-positive⁼²⁰before neurogenesis (10)=20 (Fig. 1).=20 Coincident with their exitfrom the cell cycle, neurons = down-regulate nestin and expressdistinct intermediate=20 filaments. This transition has also beenobserved in = vitro=20 where precursor cells proliferate and differentiate⁼into=20 neurons (11-16)=20 and glia (17).=20
Fig. 1. A transgenic mid-gestation mouse fetus = showing=20 the expression (blue) in CNS stem cells of a reporter gene under = control=20 of750 base pairs of the second intron of the = nestin gene.=20 The approachis described in detail in (9).⁼²⁰[View = Larger Version of this Image (74K GIF file)]

Confirming the results of in vivo fate mapping, lineage = experiments in=20 vitro show that neurons and glia can be derived froma = common=20 fetal precursor cell (12,=20 13,=20 15,=20 16,=20 18-20)=20 (Fig.2).=20 The adult nervous system also contains multipotential = precursors⁼²⁰for neurons, astrocytes, and oligodendrocytes (13,=20 16,=20 18-20).⁼²⁰Cultured cells from both the fetal and adult CNS that have=20 proliferatedin vitro can differentiate to show = morphological=20 and electrophysiologicalfeatures characteristic of = neurons:=20 regenerative action potentialsand synaptic structures = (16,=20 21)=20 (Fig. 3).=20 These data showthe multipotential nature of cells = derived from=20 the CNS.
Fig. 2. The differentiation of adult CNS stem = cell=20 clones: (A) neurons (blue) and astrocytes (red); (B) = oligodendrocytes(blue) and astrocytes (red). Scale = bars:=20 25 =B5m. (C) The proportionof cells of different = types in=20 fetal stem cell clones: ( $3D"bullet$ )=20 neurons,( $3D"circle$ )=20 astrocytes, and (+) oligodendrocytes. The proportion of = neurons⁼²⁰that differentiates in a clone is constant, independent of=20 clonesize. The same proportion of neurons = differentiates in=20 adult andfetal stem cell clones. Data taken from (20).⁼²⁰[View = Larger Version of this Image (71K GIF file)]

Fig. 3. Neuronal differentiation of CNS stem = cells=20 derived from the embryonic day-16 hippocampus. Cells were expanded = for=20 16 daysin the presence of bFGF followed by = 21 days=20 of differentiationin the presence of BDNF = (20 ng/ml).=20 (A) Staining with antibodyto synapsin (green),=20 (B) staining with antibody to MAP2,and = (C) the=20 two images superimposed. Synapsin is concentratedin=20 presynaptic terminals, and MAP2, in dendrites. The culture⁼and=20 staining conditions are similar to those reported in (21).⁼²⁰[View = Larger Version of this Image (97K GIF file)]

Quantitative studies have established the homogeneity and = stability of=20 multipotent cells derived from the fetal brain (20).⁼²⁰In vitro these cells divide daily and efficiently generate=20 neuronsand glia for at least the first month of = culture. These=20 multipotentcells proliferate sufficiently in vitro to = account=20 for the largenumbers of cells present in the mammalian = brain=20 at birth (10).⁼²⁰These cells can be considered to be stem cells because they=20 fulfillthe criteria of multipotency and self-renewal.=20 Asymmetric division,which is sometimes considered to = be a=20 property of stem cells (2)⁼²⁰and may actually occur in the neuroepithelium (22),=20 does notappear to be necessary in cultured CNS stem = cells (20).⁼²⁰

Response Mechanisms and Transitions in Vitro
The = extraordinary=20 diversity of the adult vertebrate nervous system is generated from = a sheet=20 of epithelial cells over a periodof several days. = Precise=20 numbers of neurons, astrocytes, and oligodendrocytes⁼²⁰differentiate in successive waves. The spinal cord, formed = from⁼²⁰the caudal region of the neural tube, is one of the first = sites⁼²⁰of neuronal differentiation. Basic fibroblast growth factor=20 (bFGF)is one mechanism that defines rostro-caudal = identity in=20 the neuraltube (23).=20 Neuronal differentiation in the dorso-ventral axisis a = response of uncommitted cells to successive extracellular⁼²⁰signals (24).=20 Sonic hedgehog and members of the transforminggrowth=20 factor- $3D"beta$ (TGF-) family influence ventral and dorsal features⁼of=20 development in the caudal neural tube. These signals are used⁼in several cellular contexts. For example, members of the = TGF-family influence segment-specific = apoptosis in the=20 neuroepithelium(25),=20 astrocyte maturation (26),=20 the differentiation of peripheralnervous system stem = cells (27),=20 and dorso-ventral differentiationin the CNS (24).=20 These diverse effects emphasize that the actionof=20 extracellular ligands depends on the integration of multiple⁼²⁰signals by a specific responding cell.
Cell-autonomous mechanisms may also contribute to the = generation of=20 cell types in the nervous system. In the hematopoietic⁼system,=20 cell-autonomous stochastic processes are thought to generate⁼²⁰all of the mature cell types, and the specificity of=20 differentiationis a consequence of selective = mechanisms (28).=20 In such a system,specificity is obtained as a = consequence of=20 signals acting selectivelyonly after the events that = generate=20 the different cell types.There is clear evidence for = cell=20 death in the neural tube (29)⁼²⁰and growing knowledge of extra- and intracellular signals = that⁼²⁰mediate cell death (30).=20 The high rates of apoptosis duringneural development = are=20 consistent with an important role for selective⁼mechanisms in=20 the CNS.

Instructive mechanisms also occur in both the peripheral (PNS) = and=20 central nervous systems. Glial growth factor, a member⁼of the=20 heregulin-neuregulin class of factors, acts instructively⁼on=20 PNS stem cells to direct them to a Schwann cell fate (31).⁼²⁰Bone morphogenetic proteins (BMP) 2 and = 4 stimulate=20 neurogenesis,and TGF- $3D"beta$ 1 generates=20 smooth-muscle cells from the PNS stem cell(27).=20 In the CNS, ciliary neurotrophic factor (CNTF) acts = instructively⁼²⁰on the multipotential stem cell, directing it to a committed = astrocyticfate (20).=20

It has previously been shown that CNTF induces astrocytic=20 differentiation in O2-A cells (32).=20 In vitro, CNS stem cells rapidlyand efficiently = differentiate=20 into astrocytes in the presenceof CNTF (20).=20 CNTF is not a mitogen for these cells, and a transient⁼exposure=20 (48 hours) to CNTF, even in the presence of mitogen,⁼²⁰switches the differentiated state of more than 98% of the=20 uncommittedstem cells. These data suggest that, in the = absence=20 of significantcell death, stimulating the Jak-stat = system (the=20 effector of CNTF)instructs the stem cell to become an=20 astrocyte. In a recent study,BMPs promoted astrocytic=20 differentiation from cells that had beenexpanded in = vitro in=20 the presence of epidermal growth factor (26).⁼²⁰It will be interesting to establish whether BMPs and CNTF = act⁼²⁰through a common pathway at the same stage of astrocyte=20 differentiation.

Thyroid hormone (T3) is also an instructive factor causing stem = cells=20 to become lineage-restricted progenitors for oligodendrocytes⁼(20).=20 Interestingly, CNTF and T3 are both differentiation and⁼²⁰lineage-restriction factors. The differentiation of = peripheral⁼²⁰and central stem cells can be achieved without selection by = the⁼²⁰instructive action of extracellular signals. However, it = seems⁼²⁰likely that a combination of instruction and selection is = used⁼²⁰in vivo to precisely regulate precursor-product transitions = at⁼²⁰the cellular level.

The importance of selective mechanisms acting on a defined = precursor=20 cell type in brain development is best illustrated by⁼studies=20 on the differentiation of oligodendrocytes. There is evidence⁼from the optic nerve for the existence of a bipotential=20 progenitorin vitro for oligodendrocytes and type-2 = astrocytes,=20 the O-2Acell (33).=20 In addition, the differentiation of this precursorcell = could=20 be controlled by manipulation of extracellular signals.⁼Once=20 the properties of this cell had been established, it became⁼²⁰clear that a similar cell existed in the adult optic nerve = (34).⁼²⁰In tissue culture, O-2A cells respond to several factors = [bFGF,⁼²⁰platelet-derived growth factor, CNTF, neurotrophins, and = T3],⁼²⁰and many of these factors also act in vivo to increase=20 oligodendrocytenumber in the optic nerve (35).=20 These in vivo data show thatthe availability of growth = factors=20 is limiting and that cell deathis important in = regulating=20 oligodendrocyte numbers.

This summary indicates that simple ligands can regulate in = vitro the=20 transitions between stem cells and the three major cell⁼types=20 of the adult brain. However, it is not clear how many cell⁼²⁰states exist in addition to stem cells and committed=20 progenitorsfor astrocytes and oligodendrocytes. In = some cases=20 precursor-producttransitions have been defined, but = there are=20 still many aspectsof cell-type origins that are = unclear and=20 may be advanced by furtherwork in vitro. Epidermal = growth=20 factor (EGF) and bFGF have bothbeen used as mitogens = to expand=20 CNS stem cells, but EGF may notbe the optimal choice = for a=20 stem cell mitogen, as there is evidencethat EGF favors = glial=20 differentiation. In vitro EGF is a stemcell mitogen = and a=20 differentiation factor for astrocytes but nota lineage = restriction factor, suggesting that the commitment event⁼is=20 distinct from the differentiation mechanism (20).=20 However,the in vivo overexpression of EGF receptor may = induce=20 a fate shiftfrom neurons to glia rather than simply = promote=20 astrocytic differentiation(36).=20 It is clearly necessary to define the fundamental biochemical⁼differences between lineage restriction in stem cells and=20 differentiationof progenitor cells.

Another important unresolved question is whether there are=20 proliferating cells capable of giving rise to specific kinds = of⁼²⁰neuron. There is evidence for a cell of this type in the=20 postnatalcerebellum, but it is not clear whether a = committed=20 neuronal progenitoroccurs in other brain regions (37).=20 The events that generatethe pluripotent CNS stem cell = from an=20 earlier totipotent embryonicstem cell can also be = analyzed in=20 vitro, because embryonic stemcells differentiate = through a=20 nestin-positive state to form synapticallyactive = networks of=20 central neurons (38).=20 The routine differentiationof functional neurons from=20 propagated stem cells would permitdetailed analysis of = how=20 early steps in neurogenesis influencelater stages of = neuronal=20 differentiation. The challenge is toset up = experimental=20 systems where the differentiation events ofinterest = can be=20 measured efficiently.

Space and Time
The cortical neuroepithelium is a highly = polarized=20 structure. Precursor cells divide at the inner (ventricular) = surface=20 ofthe neural tube, and immature neurons migrate away = from the=20 ventricleto specific layers. As different neurons = become=20 postmitotic insequence, their laminar location is a = function=20 of the time whenthe neuron differentiated. Transplants = in=20 ferret cortex show thatappropriate, layer-specific = neuronal=20 differentiation occurs whencells derived from an early = time=20 are moved to a later stage (39).⁼²⁰Conversely, late neuronal precursors transplanted to an = earlier⁼²⁰stage host do not contribute efficiently to early neuronal=20 fatesbut rather exhibit laminar positions appropriate = for=20 late-generatedneurons (40).=20 This evidence supports a model where a neuronbecomes = committed=20 to a particular laminar fate in the ventricularzone at = the=20 time of withdrawal from the cell cycle. Thus, it isthe = timing=20 of the exit from the cycle that is thought to implement⁼two=20 distinct commitment events. In this scenario, the postmitotic⁼neuron is locked into a specific fate, and the remaining=20 precursorsare also irrevocably changed.=20
It is not known what specifies the regional identity of the = different=20 areas of the CNS. There are complex patterns of expression⁼of=20 both cell surface signals and transcriptional regulators in⁼the=20 developing neuroepithelium long before neurons themselves⁼²⁰differentiate (41).=20 But there could be different stem cellsfor different = brain=20 regions. Gene deletion experiments in miceillustrate = that=20 whole sections of the brain can be eliminatedwith = relatively=20 little perturbation of the development of adjacent⁼brain=20 regions (42).=20 Although these results are startling, theydo not = establish=20 whether neuronal precursor cells are irreversibly⁼committed to=20 distinct regional fates. To establish commitment,we = must give=20 cells an opportunity to choose another regional fate.⁼In the=20 developing chick, a duplication of a brain region can be⁼²⁰obtained by the local application of FGF8 (43).=20 This resultsuggests that single factors are sufficient = to bias=20 the differentiationcascade and establish major = regional=20 features of the CNS.

The rhombomeres of the hindbrain are a good example of the=20 compartmental arrangement of the neuroepithelium (44).=20 Althoughit was first thought that cells were = prohibited from=20 crossingthe boundaries between rhombomeric = compartments, fate=20 mappingin vivo now suggests that cells do move from = one=20 compartment toanother at a low frequency (45).=20 In other brain regions, neuronalprecursors also = migrate over=20 great distances (46).=20 When thelocation of rhombomeres was altered by tissue = grafts,=20 rhombomere-specificHox gene expression was = respecified=20 by as yet undefined anterior-posteriorcontrol systems = (47).=20 In these transplant experiments, piecesof tissue were=20 rearranged, making it hard to interpret the responses⁼of single=20 cells. It will be interesting to directly test the plasticity⁼of isolated rhombomeric cells by transplanting dissociated=20 cellsfrom one rhombomere to another.

Grafting experiments with cell lines from the hippocampus = support a=20 model in which local signals in the neuroepithelium at⁼the time=20 of neurogenesis give rise to region-specific neuronal⁼subtypes.=20 Immortalized nestin-positive hippocampal cells transplanted⁼to=20 the developing cerebellum differentiated into typical = cerebellar⁼²⁰neurons (48).=20 Transplants of primary striatal cells into the⁼developing=20 cerebral cortex also showed a switch to the locally⁼appropriate=20 fate (49),=20 suggesting that the plasticity in cellfate shown with = immortal=20 cells was not an artifact of immortalization.In = conceptually=20 similar experiments, primary cerebellar cellsderived = from mice=20 expressing the lacZ reporter gene under a = neuron-specific⁼²⁰promoter were grafted into the hippocampus of neonatal rats = or⁼²⁰wild-type mice. The grafted cells acquired morphological and = immunohistochemicalfeatures of hippocampal granule = neurons (50).=20 The grafted andhost neurons also showed kinetics of = induction=20 identical to thoseof the immediate early gene = c-fos=20 after intraperitoneal injectionof neurotransmitter = agonists=20 and antagonists (50).=20 These datasuggest that immortal and primary = neuroepithelial=20 precursor cellsgrafted to new sites generate = region-specific=20 neurons in responseto local cues.

A major limitation of postnatal transplantation studies was = that=20 heterotopic neuronal integration occurred efficiently only⁼when=20 donor cells were introduced into the few sites that continued⁼to generate neurons in the newborn animal. This limited=20 spectrumof accessible regions was dramatically = increased by=20 transplantingneural cells across the uterine wall into = the=20 embryonic mammalianbrain (49,=20 51,=20 52).=20 When genetically labeled mouse telencephalic⁼neuroepithelial=20 cells were simply deposited in the ventricles,large = numbers of=20 grafted cells were subsequently found incorporatedinto = many=20 sites in the host brain. The transplanted cells migrated⁼in=20 accordance with known pathways and incorporated into = telencephalic,⁼²⁰diencephalic, and mesencephalic regions (52).=20 Surprisingly,cells derived from the dorsal and ventral = forebrain incorporatedinto homotopic and many = heterotopic=20 brain regions in a similarfashion. After migration, = the cells=20 acquired morphological andantigenic features = appropriate for=20 neurons in their new environment(Fig. 4).=20 The fact that striatal precursors can give rise to cortical,⁼²⁰thalamic, and even tectal neurons illustrates that the = regional⁼²⁰heterogeneity of the brain results primarily from = extracellular⁼²⁰signals acting on precursors during neuronal migration and=20 differentiation.These results indicate that the = activation of=20 different signalingpathways in uncommitted stem cells=20 generates the spatial heterogeneityof neurons seen in = the CNS.=20
Fig. 4. Genetically labeled cells differentiate = into=20 hippocampal CA1 pyramidal neurons. The donor cells were derived = from the=20 embryonicday-14 cortical neuroepithelium of a = transgenic mouse=20 carryinga lacZ reporter gene. They were placed = into the=20 telencephalicvesicles of an E18 rat, where they = incorporated=20 into the hosthippocampus and differentiated into = granule and=20 pyramidal neurons.The grafted cells can be identified = by the=20 blue lacZ signal. Datataken from (52).=20 Scale bar: 50 =B5m.[View = Larger Version of this Image (130K GIF file)]

Stem Cells and Disease in the Adult Nervous System
It is = important=20 to define the types of precursor cells that give rise to the = neurons=20 generated in the adult CNS (53,=20 54).⁼²⁰Cells from the adult brain proliferate and differentiate = into⁼²⁰neurons and glia in tissue culture (13,=20 14,=20 16,=20 55)=20 withthe same efficiency for neuronal differentiation = as found=20 in fetalstem cells and the same responses to = extracellular=20 ligands (20).⁼²⁰For example, 50% of the cells differentiate into neurons, = and⁼²⁰glial differentiation is strongly enhanced in response to = CNTF⁼²⁰and T3 in fetal and adult stem cells. Thus, similar general=20 mechanismscontrol the differentiation of stem cells = from fetal=20 or adultbrain. In contrast to this apparent = homogeneity in=20 vitro, thebehavior of cells in the adult proliferative = zones=20 in vivo ismore difficult to define. Nevertheless, = precursor=20 cells in theadult forebrain have been intensely = studied (19,=20 54,=20 56).⁼²⁰The proliferation of these cells can be stimulated by the=20 directapplication of mitogenic growth factors in vivo, = and in=20 animalstreated in this way, proliferating cells in the = subventricularzone differentiate into neurons and glia = (57).=20 However, in vivoless than 3% of the proliferating = cells=20 labeled with bromodeoxyuridinedifferentiate into = neurons. The=20 discrepancy between the efficientneuronal = differentiation of=20 adult stem cells in vitro and theirinefficient = differentiation=20 in vivo is a critical but unresolvedquestion for the = field.=20 Thus, the lack of differentiating neuronsmay not be a=20 consequence of the lack of cells with the appropriate⁼potential=20 but rather a function of the signaling environment in⁼the adult=20 brain. However, a careful analysis of adult stem cells⁼has only=20 just begun, and we cannot yet rule out cell-autonomous⁼²⁰restrictions that make the adult stem cells distinct from = their⁼²⁰fetal counterparts.=20
There is traditionally a close interaction between fundamental = and=20 clinical goals in the study of stem cells (58).=20 The identificationof extracellular proteins that = regulate the=20 differentiation ofmultipotent cells derived from the = adult=20 brain has implicationsfor therapies targeted at=20 neurodegenerative disease. The increasedinterest in=20 extracellular signals acting on plastic cells during⁼²⁰development fits well with the massive effort mounted in the = biotechnologycommunity to develop treatments for=20 neurodegenerative diseasebased on the delivery of = neurotrophic=20 proteins. In vitro neuronalsurvival assays were often = used in=20 the initial identificationof neurotrophic factors. = These=20 factors were then rapidly testedin animal models of=20 neurodegenerative disease. The long-term deliveryof = proteins=20 in the brain is a major goal in gene therapy. Transplantation⁼of cells engineered to produce growth factors shows the=20 potentialof grafted cells as vectors for protein = delivery (59).=20 However,the complexity of neurotrophic signals still=20 challenges the technologyfor gene manipulation and = protein=20 delivery in the CNS. There hasbeen encouraging = progress in=20 using cell lines derived from theneuroepithelium = rather than=20 fibroblasts as cellular vectors inmodels of CNS = disease.=20 Neuroepithelial cells integrate in thehost more = readily than=20 fibroblasts. This feature is an advantagefor = distributing a=20 soluble ligand more widely in the diseasedbrain (60)=20 or correcting a general biochemical deficit in theCNS = (61).=20

It is possible to generate many different immortal cell lines = from the=20 developing CNS. These cells can express characteristics⁼of stem=20 cells (48,=20 62),=20 neurons (63,=20 64),=20 or glia (17,⁼²⁰65).=20 Immortalized neuroepithelial stem cells can show extensive⁼²⁰morphological differentiation into neurons when they are=20 graftedinto the developing (48,=20 62)=20 or adult brain (64).=20 The differentiationof genetically labeled immortal = cells into=20 neurons when implantedinto the adult brain is notable = because=20 it hints that neuronalreplacement in the adult is not = only=20 possible but might becomesimple. In most cases,=20 immortalization has been achieved by incorporating⁼oncogenes=20 into a primary cell, which is, of course, not advisable⁼for=20 actual clinical use. However, the CRE-loxP system may be = useful⁼²⁰for removing the immortalizing oncogene before implantation = (66).⁼²⁰

More recently, the field has shifted away from the use of=20 oncogene-immortalized cells toward the grafting of primary = cells⁼²⁰expanded in vitro. An example of this development is an=20 experimentsuggesting that primary adult cells derived = from the=20 hippocampusand cultured for long periods in vitro can = still=20 differentiateinto neurons when re-implanted into the = migratory=20 pathway usedto replenish neurons in the adult = olfactory bulb=20 (67).=20 Althoughthis field is still technically demanding, = these and=20 other resultsdiscussed here suggest that further = experimental=20 work should bedirected at ambitious cell therapies = based on=20 both primary andimmortal cells derived from the=20 neuroepithelium. Clinical trialsshow that neuron = replacement=20 therapies for neurodegenerative diseases,such as = Parkinson's=20 and Huntington's disease, are feasible (68).⁼²⁰Neural grafting is currently limited by a number of factors, = includingthe lack of suitable donor material and the = full=20 integration ofthe grafted cells. In vitro expansion = and=20 manipulation of cellsfrom the neuroepithelium will = provide a=20 range of well-characterizedcells for transplant-based=20 strategies for neurodegenerative disease(69).=20 Experimental grafts in animal models suggest that the⁼²⁰integration of grafted neurons into the circuitry of the = host⁼²⁰may be possible (50,=20 52,=20 62,=20 64,=20 69).=20 Appropriate pretreatmentof the host brain may be = required for=20 efficient neuronal differentiationby grafted = precursors (70).=20 For clinical applications, cellculture offers an = important=20 opportunity to use sophisticated geneticsin cell-based = therapies for neural disease.

The clinical significance of stem cell biology extends beyond=20 cell-based therapies. The dynamics of cell organization is = also⁼²⁰critically relevant to a systematic understanding of CNS = tumors⁼²⁰and of physical injury to the brain. Two examples of nestin=20 expressionin the adult brain illustrate this point. In = addition to beingexpressed in adult stem cells, nestin = is also=20 found in CNS tumors(71)=20 and reactive astrocytes (72).=20 These observations raisethe interesting question of = the extent=20 of similarity between thesenestin-positive cells and = CNS stem=20 cells. The proliferation andmigration of CNS tumor = cells are=20 their two most damaging features.It is tempting to = speculate=20 that the self-renewing cell in a CNStumor is similar = to the=20 stem cells found in the fetal and adultCNS.

These examples illustrate the much more general point that = there will=20 be a wide clinical impact resulting from increased knowledge⁼of=20 the mechanisms that control the transitions between cell = types⁼²⁰in the adult CNS. The clear-cut properties of dissociated = CNS⁼²⁰stem cells in culture show that in vitro technology can be = used⁼²⁰to define, at the cellular and molecular levels, the steps = in⁼²⁰fate choice. The presence in the adult of multipotential = cells⁼²⁰similar to the fetal stem cell emphasizes the importance of=20 extracellularsignals acting on stem cells throughout = the=20 mammalian life cycle.As our understanding of the = nature of=20 these signals grows, therapieswill be developed in = which the=20 responses of normal and diseasedstem cells will be = manipulated=20 to clinically useful ends.

REFERENCES AND NOTES

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| Abstract= =20 =BB | Full Text=20 =BB | PDF = =BB

Musculoskeletal Differentiation of Cells Derived from Human=20 Embryonic Germ Cells.=20
M. S. Kim, N. S. Hwang, J. Lee, T.-K. Kim, K. Leong, M. J.=20 Shamblott, J. Gearhart, and J. Elisseeff (2005)
Stem = Cells=20 23, 113-123
| Abstract=20 =BB | Ful= l=20 Text =BB | PDF = =BB=20

Neural progenitor cells from postmortem adult human retina.=20
E J Mayer, D A Carter, Y Ren, E H Hughes, C M Rice, C A = Halfpenny, N=20 J Scolding, and A D Dick (2005)
Br. J. Ophthalmol.=20 89, 102-106
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

Radial glia give rise to adult neural stem cells in the=20 subventricular zone.=20
F. T. Merkle, A. D. Tramontin, J. M. Garcia-Verdugo, and A.=20 Alvarez-Buylla (2004)
PNAS 101, = 17528-17532=20
| Abstract=20 =BB | Full = Text =BB=20 | PDF = =BB

Intracerebral Transplantation of Adult Mouse Neural = Progenitor Cells=20 into the Niemann-Pick-A Mouse Leads to a Marked Decrease in = Lysosomal=20 Storage Pathology.=20
L. S. Shihabuddin, S. Numan, M. R. Huff, J. C. Dodge, J. = Clarke, S.=20 L. Macauley, W. Yang, T. V. Taksir, G. Parsons, M. A. Passini, = et=20 al. (2004)
J. Neurosci. 24,=20 10642-10651
| Abstra= ct=20 =BB | Full Text = =BB | PDF = =BB=20

Absence of Major Histocompatibility Complex Class I on = Neural Stem=20 Cells Does Not Permit Natural Killer Cell Killing and Prevents=20 Recognition by Alloreactive Cytotoxic T Lymphocytes In Vitro.=20
M. Mammolenti, S. Gajavelli, P. Tsoulfas, and R. Levy=20 (2004)
Stem Cells 22, 1101-1110=20
| Abstract=20 =BB | Fu= ll=20 Text =BB | PDF=20 =BB

Conserved POU Binding DNA Sites in the Sox2 Upstream = Enhancer=20 Regulate Gene Expression in Embryonic and Neural Stem Cells.=20
R. Catena, C. Tiveron, A. Ronchi, S. Porta, A. Ferri, L. = Tatangelo,=20 M. Cavallaro, R. Favaro, S. Ottolenghi, R. Reinbold, et = al.=20 (2004)
J. Biol. Chem. 279, = 41846-41857=20
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Roles of lipid rafts in integrin-dependent adhesion and = gp130=20 signalling pathway in mouse embryonic neural precursor cells.=20
M. Yanagisawa, K. Nakamura, and T. Taga (2004)
Genes = Cells=20 9, 801-809
| A= bstract=20 =BB | Full = Text =BB | PDF = =BB=20

Sox2 deficiency causes neurodegeneration and impaired = neurogenesis=20 in the adult mouse brain.=20
A. L. M. Ferri, M. Cavallaro, D. Braida, A. Di Cristofano, = A. Canta,=20 A. Vezzani, S. Ottolenghi, P. P. Pandolfi, M. Sala, S. DeBiasi, = et=20 al. (2004)
Development 131, = 3805-3819=20
| Abstr= act=20 =BB | Full = Text=20 =BB | PDF = =BB=20

Gene Expression Changes in the Course of Neural Progenitor = Cell=20 Differentiation.=20
U. Gurok, C. Steinhoff, B. Lipkowitz, H.-H. Ropers, C. = Scharff, and=20 U. A. Nuber (2004)
J. Neurosci. 24, = 5982-6002
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

Neuropoietin, a new IL-6-related cytokine signaling through = the=20 ciliary neurotrophic factor receptor.=20
D. Derouet, F. Rousseau, F. Alfonsi, J. Froger, J. Hermann, = F.=20 Barbier, D. Perret, C. Diveu, C. Guillet, L. Preisser, et = al.=20 (2004)
PNAS 101, 4827-4832 =
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Mitotic and neurogenic effects of dehydroepiandrosterone = (DHEA) on=20 human neural stem cell cultures derived from the fetal cortex.=20
M. Suzuki, L. S. Wright, P. Marwah, H. A. Lardy, and C. N. = Svendsen=20 (2004)
PNAS 101, 3202-3207 =
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Retinoic acid induces alveolar regeneration in the adult = mouse lung.=20
M. Hind and M. Maden (2004)
Eur. Respir. J.=20 23, 20-27
| Abstract= =20 =BB | Full Text=20 =BB | PDF = =BB

Cellular and Genetic Characterization of Human Adult Bone=20 Marrow-Derived Neural Stem-Like Cells: A Potential Antiglioma = Cellular=20 Vector.=20
J. Lee, A. G. Elkahloun, S. A. Messina, N. Ferrari, D. Xi, = C. L.=20 Smith, R. Cooper Jr., P. S. Albert, and H. A. Fine = (2003)
Cancer=20 Res. 63, 8877-8889
| Abstract=20 =BB | Fu= ll=20 Text =BB | PDF=20 =BB

Searching for Stem/Progenitor Cells in the Adult Mouse = Kidney.=20
F. Lin and P. Igarashi (2003)
J. Am. Soc. Nephrol.=20 14, 3290-3292
| Full = Text =BB=20 | PDF =BB =

Evidence for neurogenesis in the adult mammalian substantia = nigra.=20
M. Zhao, S. Momma, K. Delfani, M. Carlen, R. M. Cassidy, C. = B.=20 Johansson, H. Brismar, O. Shupliakov, J. Frisen, and A. M. = Janson=20 (2003)
PNAS 100, 7925-7930 =
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Cell Cycle Regulation in Retinal Progenitors by Glia-Derived = Neurotrophic Factor and Docosahexaenoic Acid.=20
M. F. Insua, A. Garelli, N. P. Rotstein, O. L. German, A. = Arias, and=20 L. E. Politi (2003)
Invest. Ophthalmol. Vis. Sci.=20 44, 2235-2244
| Abstract = =BB=20 | Full = Text =BB=20 | PDF =BB =

Autocrine/Paracrine Activation of the GABAA Receptor = Inhibits the=20 Proliferation of Neurogenic Polysialylated Neural Cell Adhesion=20 Molecule-Positive (PSA-NCAM+) Precursor Cells from Postnatal = Striatum.=20
L. Nguyen, B. Malgrange, I. Breuskin, L. Bettendorff, G. = Moonen, S.=20 Belachew, and J.-M. Rigo (2003)
J. Neurosci.=20 23, 3278-3294
| Abstract= =20 =BB | Full Text=20 =BB | PDF = =BB

Neural Stem Cells: An Overview.=20
R. Galli, A. Gritti, L. Bonfanti, and A. L. Vescovi=20 (2003)
Circ. Res. 92, 598-608=20
| Abs= tract=20 =BB | Full=20 Text =BB | PDF = =BB=20

Human embryonic stem cells: research, ethics and policy.=20
G. d. Wert and C. Mummery (2003)
Hum. Reprod.=20 18, 672-682
| A= bstract=20 =BB | Full = Text =BB | PDF = =BB=20

The new stem cell biology: something for everyone.=20
S L Preston, M R Alison, S J Forbes, N C Direkze, R Poulsom, = and N A=20 Wright (2003)
Mol. Pathol. 56, = 86-96=20
| Abstract = =BB | Full = Text=20 =BB | PDF = =BB

Fibroblast growth factors as regulators of central nervous = system=20 development and function.=20
R. Dono (2003)
Am J Physiol Regulatory Integrative = Comp=20 Physiol 284, R867-R881
| Ab= stract=20 =BB | Full=20 Text =BB | PDF = =BB=20

Generation of different fates from multipotent muscle stem = cells.=20
M. R. Wada, M. Inagawa-Ogashiwa, S. Shimizu, S. Yasumoto, = and N.=20 Hashimoto (2003)
Development 129, = 2987-2995=20
| Abstr= act=20 =BB | Full = Text=20 =BB | PDF = =BB=20

Notch1 is required for neuronal and glial differentiation in = the=20 cerebellum.=20
S. Lutolf, F. Radtke, M. Aguet, U. Suter, and V. Taylor=20 (2003)
Development 129, 373-385=20
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

Transplanted bone marrow generates new neurons in human = brains.=20
E. Mezey, S. Key, G. Vogelsang, I. Szalayova, G. D. Lange, = and B.=20 Crain (2003)
PNAS 100, 1364-1369=20
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Locally Born Olfactory Bulb Stem Cells Proliferate in = Response to=20 Insulin-Related Factors and Require Endogenous Insulin-Like = Growth=20 Factor-I for Differentiation into Neurons and Glia.=20
C. Vicario-Abejon, M. J. Yusta-Boyo, C. Fernandez-Moreno, = and F. de=20 Pablo (2003)
J. Neurosci. 23, = 895-906=20
| Abstract = =BB | Full = Text=20 =BB | PDF = =BB

Local and Global Spontaneous Calcium Events Regulate Neurite = Outgrowth and Onset of GABAergic Phenotype during Neural = Precursor=20 Differentiation.=20
F. Ciccolini, T. J. Collins, J. Sudhoelter, P. Lipp, M. J. = Berridge,=20 and M. D. Bootman (2003)
J. Neurosci. = 23,=20 103-111
| Abstract = =BB | Full = Text=20 =BB | PDF = =BB

Differential modulation of BMP signaling promotes the = elaboration of=20 cerebral cortical GABAergic neurons or oligodendrocytes from a = common=20 sonic hedgehog-responsive ventral forebrain progenitor species.=20
S.-Y. Yung, S. Gokhan, J. Jurcsak, A. E. Molero, J. J. = Abrajano, and=20 M. F. Mehler (2002)
PNAS 99, = 16273-16278=20
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Extracellular Signal-Regulated Protein Kinase Signaling Is = Uncoupled=20 From Initial Differentiation of Central Nervous System Stem = Cells to=20 Neurons.=20
M. Enarsson, A. Erlandsson, H. Larsson, and K. = Forsberg-Nilsson=20 (2002)
Mol. Cancer Res. 1, 147-154=20
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

Strategies for recovery and regeneration after brain and = spinal cord=20 injury.=20
C H Tator (2002)
Inj. Prev. 8, = iv33-36=20
| Ab= stract=20 =BB | Full=20 Text =BB

CEMENTUM AND PERIODONTAL WOUND HEALING AND REGENERATION.=20
W. J. Grzesik and A.S. Narayanan (2002)
Crit. Rev. = Oral.=20 Biol. Med. 13, 474-484
| Abst= ract=20 =BB | Full = Text=20 =BB | PDF = =BB=20

Fetal Brain Progenitor Cells Transdifferentiate to Fates = Outside the=20 Nervous System.=20
H. S. U, W. Alilain, and F. Saljooque (2002)
Mol. = Endocrinol.=20 16, 2645-2656
| Abs= tract=20 =BB | Full=20 Text =BB | PDF = =BB=20

Neural stem cell heterogeneity demonstrated by molecular = phenotyping=20 of clonal neurospheres.=20
O. N. Suslov, V. G. Kukekov, T. N. Ignatova, and D. A. = Steindler=20 (2002)
PNAS 99, 14506-14511 =
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Reactivation of Latent Cytomegalovirus Infection in Mouse = Brain=20 Cells Detected after Transfer to Brain Slice Cultures.=20
Y. Tsutsui, H. Kawasaki, and I. Kosugi (2002)
J. = Virol.=20 76, 7247-7254
| Abstract = =BB=20 | Full = Text =BB=20 | PDF =BB =

Role for FGFR2IIIb-mediated signals in controlling = pancreatic=20 endocrine progenitor cell proliferation.=20
L. Elghazi, C. Cras-Meneur, P. Czernichow, and R. Scharfmann = (2002)
PNAS 99, 3884-3889 =
| Abstract = =BB=20 | Full = Text =BB=20 | PDF =BB =

Long-Term Survival and Glial Differentiation of the = Brain-Derived=20 Precursor Cell Line RN33B after Subretinal Transplantation to = Adult=20 Normal Rats.=20
A. B. Wojciechowski, U. Englund, C. Lundberg, and K. = Warfvinge=20 (2002)
Stem Cells 20, 163-173=20
| Abstract=20 =BB | Ful= l=20 Text =BB | PDF = =BB=20

Thyroid hormone activates oligodendrocyte precursors and = increases a=20 myelin-forming protein and NGF content in the spinal cord during = experimental allergic encephalomyelitis.=20
L. Calza, M. Fernandez, A. Giuliani, L. Aloe, and L. = Giardino=20 (2002)
PNAS
| =20 Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Multipotent Neural Stem Cells Reside into the Rostral = Extension and=20 Olfactory Bulb of Adult Rodents.=20
A. Gritti, L. Bonfanti, F. Doetsch, I. Caille, A. = Alvarez-Buylla, D.=20 A. Lim, R. Galli, J. M. G. Verdugo, D. G. Herrera, and A. L. = Vescovi=20 (2002)
J. Neurosci. 22, 437-445=20
| Abstract = =BB | Full = Text=20 =BB | PDF = =BB

Emx2 regulates the proliferation of stem cells of the adult=20 mammalian central nervous system.=20
R. Galli, R. Fiocco, L. De Filippis, L. Muzio, A. Gritti, S. = Mercurio, V. Broccoli, M. Pellegrini, A. Mallamaci, and A. L. = Vescovi=20 (2002)
Development 129, 1633-1644=20
| Abstra= ct=20 =BB | Full Text = =BB | PDF = =BB=20

The Minimum Number of Neurons in the Central Olfactory = Pathway in=20 Relation to its Function: a Retrograde Fiber Tracing Study.=20
N. Fukushima, S. Oikawa, K. Yokouchi, K. Kawagishi, and T. = Moriizumi=20 (2002)
Chem Senses 27, 1-6 =
| Abs= tract=20 =BB | Full=20 Text =BB | PDF = =BB=20

Transcription Factor Expression and Notch-Dependent = Regulation of=20 Neural Progenitors in the Adult Rat Spinal Cord.=20
S.-i. Yamamoto, M. Nagao, M. Sugimori, H. Kosako, H. = Nakatomi, N.=20 Yamamoto, H. Takebayashi, Y.-i. Nabeshima, T. Kitamura, G. = Weinmaster,=20 et al. (2001)
J. Neurosci. = 21,=20 9814-9823
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

The Fate of Heterotopically Grafted Neural Precursor Cells = in the=20 Normal and Dystrophic Adult Mouse Retina.=20
S. Pressmar, M. Ader, G. Richard, M. Schachner, and U. = Bartsch=20 (2001)
Invest. Ophthalmol. Vis. Sci. = 42,=20 3311-3319
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Cell Cycle Regulation during Mouse Olfactory Neurogenesis.=20
M.-E. Legrier, A. Ducray, A. Propper, M. Chao, and A. = Kastner=20 (2001)
Cell Growth Differ. 12, = 591-601=20
| Abstr= act=20 =BB | Full = Text=20 =BB | PDF = =BB=20

Neuroprotection through Delivery of Glial Cell Line-Derived=20 Neurotrophic Factor by Neural Stem Cells in a Mouse Model of = Parkinson's=20 Disease.=20
P. Akerud, J. M. Canals, E. Y. Snyder, and E. Arenas=20 (2001)
J. Neurosci. 21, 8108-8118=20
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

Immature Neurons From CNS Stem Cells Proliferate in Response = to=20 Platelet-Derived Growth Factor.=20
A. Erlandsson, M. Enarsson, and K. Forsberg-Nilsson = (2001)
J.=20 Neurosci. 21, 3483-3491
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

BMP2-mediated alteration in the developmental pathway of = fetal mouse=20 brain cells from neurogenesis to astrocytogenesis.=20
K. Nakashima, T. Takizawa, W. Ochiai, M. Yanagisawa, T. = Hisatsune,=20 M. Nakafuku, K. Miyazono, T. Kishimoto, R. Kageyama, and T. Taga = (2001)
PNAS
| =20 Abstract=20 =BB | Full = Text =BB=20

Neurogenesis in dentate subgranular zone and rostral = subventricular=20 zone after focal cerebral ischemia in the rat.=20
K. Jin, M. Minami, J. Q. Lan, X. O. Mao, S. Batteur, R. P. = Simon,=20 and D. A. Greenberg (2001)
PNAS 98, = 4710-4715
| Abstract = =BB=20 | Full = Text =BB=20 | PDF =BB =

Circulating Insulin-Like Growth Factor I Mediates = Exercise-Induced=20 Increases in the Number of New Neurons in the Adult Hippocampus. =
J. L. Trejo, E. Carro, and I. Torres-Aleman (2001)
J. = Neurosci. 21, 1628-1634
| Abstract= =20 =BB | Full Text=20 =BB | PDF = =BB

DNA damage-induced neural precursor cell apoptosis requires = p53 and=20 caspase 9 but neither Bax nor caspase 3.=20
C D'Sa-Eipper, J. Leonard, G Putcha, T. Zheng, R. Flavell, P = Rakic,=20 K Kuida, and K. Roth (2001)
Development=20 128, 137-146
| Abstrac= t=20 =BB | PDF = =BB=20

Direct isolation of human central nervous system stem cells. =
N. Uchida, D. W. Buck, D. He, M. J. Reitsma, M. Masek, T. V. = Phan,=20 A. S. Tsukamoto, F. H. Gage, and I. L. Weissman = (2000)
PNAS=20 97, 14720-14725
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Turning Blood into Brain: Cells Bearing Neuronal Antigens = Generated=20 in Vivo from Bone Marrow.=20
E. Mezey, K. J. Chandross, G. Harta, R. A. Maki, and S. R. = McKercher=20 (2000)
Science 290, 1779-1782=20
| Abs= tract=20 =BB | Full=20 Text =BB

Region-specific differentiation of neural tube-derived = neuronal=20 restricted progenitor cells after heterotopic transplantation.=20
H. Yang, T. Mujtaba, G. Venkatraman, Y. Y. Wu, M. S. Rao, = and M. B.=20 Luskin (2000)
PNAS 97, 13366-13371=20
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

From the Cover: Neural stem cells display extensive tropism = for=20 pathology in adult brain: Evidence from intracranial gliomas.=20
K. S. Aboody, A. Brown, N. G. Rainov, K. A. Bower, S. Liu, = W. Yang,=20 J. E. Small, U. Herrlinger, V. Ourednik, P. McL. Black, et = al.=20 (2000)
PNAS 97, 12846-12851 =
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Manipulating the onset of cell cycle withdrawal in = differentiated=20 erythroid cells with cyclin-dependent kinases and inhibitors.=20
I. Matushansky, F. Radparvar, and A. I. Skoultchi=20 (2000)
Blood 96, 2755-2764 =
| Abstract=20 =BB | Full=20 Text =BB | = PDF=20 =BB

Enhanced Proliferation, Survival, and Dopaminergic = Differentiation=20 of CNS Precursors in Lowered Oxygen.=20
L. Studer, M. Csete, S.-H. Lee, N. Kabbani, J. Walikonis, B. = Wold,=20 and R. McKay (2000)
J. Neurosci. = 20,=20 7377-7383
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

REST-VP16 activates multiple neuronal differentiation genes = in human=20 NT2 cells.=20
A. Immaneni, P. Lawinger, Z. Zhao, W. Lu, L. Rastelli, J. H. = Morris,=20 and S. Majumder (2000)
Nucleic Acids Res.=20 28, 3403-3410
| Ab= stract=20 =BB | Full=20 Text =BB | PDF = =BB=20

Generalized Potential of Adult Neural Stem Cells.=20
D. L. Clarke, C. B. Johansson, J. Wilbertz, B. Veress, E. = Nilsson,=20 H. Karlstr=F6m, U. Lendahl, and J. Fris=E9n = (2000)
Science=20 288, 1660-1663
| Abs= tract=20 =BB | Full=20 Text =BB

Cell Contact Regulates Fate Choice by Cortical Stem Cells.=20
R. Y. L. Tsai and R. D. G. McKay (2000)
J. Neurosci.=20 20, 3725-3735
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

Peripheral Infusion of IGF-I Selectively Induces = Neurogenesis in the=20 Adult Rat Hippocampus.=20
M. A. I. Aberg, N. D. Aberg, H. Hedbacker, J. Oscarsson, and = P. S.=20 Eriksson (2000)
J. Neurosci. 20, = 2896-2903=20
| Abstract= =20 =BB | Full Text=20 =BB | PDF = =BB

Retinal Stem Cells in the Adult Mammalian Eye.=20
V. Tropepe, B. L. Coles, B. J. Chiasson, D. J. Horsford, A. = J. Elia,=20 R. R. McInnes, and D. van der Kooy (2000)
Science=20 287, 2032-2036
| Abs= tract=20 =BB | Full=20 Text =BB

Septamer Element-Binding Proteins in Neuronal and Glial=20 Differentiation.=20
A. Dobi, M. Palkovits, C. G. Palkovits, M. A. Ring, and D. = v.=20 Agoston (2000)
J. Neurosci. 20, = 1073-1084=20
| Abstract= =20 =BB | Full Text=20 =BB | PDF = =BB

Sox2 regulatory sequences direct expression of a (beta)-geo=20 transgene to telencephalic neural stem cells and precursors of = the mouse=20 embryo, revealing regionalization of gene expression in CNS stem = cells.=20
M. Zappone, R Galli, R Catena, N Meani, S De Biasi, E = Mattei, C=20 Tiveron, A. Vescovi, R Lovell-Badge, S Ottolenghi, et = al.=20 (2000)
Development 127, 2367-2382=20
| Abstr= act=20 =BB | PDF = =BB=20

Brain Plasticity and Stroke Rehabilitation : The Willis = Lecture.=20
B. B. Johansson (2000)
Stroke = 31,=20 223-230
| Abst= ract=20 =BB | Full = Text=20 =BB | PDF = =BB=20

Neurotransplantation of magnetically labeled oligodendrocyte = progenitors: Magnetic resonance tracking of cell migration and=20 myelination.=20
J. W. M. Bulte, S.-C. Zhang, P. van Gelderen, V. Herynek, E. = K.=20 Jordan, I. D. Duncan, and J. A. Frank (1999)
PNAS=20 96, 15256-15261
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Primary CA1 and conditionally immortal MHP36 cell grafts = restore=20 conditional discrimination learning and recall in marmosets = after=20 excitotoxic lesions of the hippocampal CA1 field.=20
D. Virley, R. M. Ridley, J. D. Sinden, T. R. Kershaw, S. = Harland, T.=20 Rashid, S. French, P. Sowinski, J. A. Gray, P. L. Lantos, et = al. (1999)
Brain 122, = 2321-2335=20
| Abstract=20 =BB | Ful= l=20 Text =BB | PDF = =BB=20

Astroglial Differentiation of Cortical Precursor Cells = Triggered by=20 Activation of the cAMP-Dependent Signaling Pathway.=20
M. F. McManus, L.-C. Chen, I. Vallejo, and M. Vallejo=20 (1999)
J. Neurosci. 19, 9004-9015=20
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

Fibroblast Growth Factor-2 Activates a Latent Neurogenic = Program in=20 Neural Stem Cells from Diverse Regions of the Adult CNS.=20
T. D. Palmer, E. A. Markakis, A. R. Willhoite, F. Safar, and = F. H.=20 Gage (1999)
J. Neurosci. 19, = 8487-8497=20
| Abstrac= t=20 =BB | Full Text=20 =BB | PDF = =BB=20

Expression of oligodendrocyte progenitor cell antigens by = gliomas:=20 Implications for the histogenesis of brain tumors.=20
Y. Shoshan, A. Nishiyama, A. Chang, S. Mork, G. H. Barnett, = J. K.=20 Cowell, B. D. Trapp, and S. M. Staugaitis (1999)
PNAS=20 96, 10361-10366
| Abstract=20 =BB | Full = Text =BB=20 | PDF =BB =

Neural Stem Cells as Engraftable Packaging Lines Can Mediate = Gene=20 Delivery to Microglia: Evidence from Studying Retroviral = env-Related=20 Neurodegeneration.=20
W. P. Lynch, A. H. Sharpe, and E. Y. Snyder (1999)
J. = Virol.=20 73, 6841-6851
| Abstract = =BB=20 | Full Text = =BB=20

Embryonic Stem Cell-Derived Glial Precursors: A Source of=20 Myelinating Transplants.=20
O. Br=FCstle, K. N. Jones, R. D. Learish, K. Karram, K. = Choudhary, O.=20 D. Wiestler, I. D. Duncan, and R. D. McKay (1999)
Science = 285, 754-756
| Abst= ract=20 =BB | Full = Text=20 =BB

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" + message + "

.=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_01F3_01C85B7A.89A68AF0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.sciencemag.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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