Glioblastoma Formation from Cell Population Depleted = of Prominin1-Expressing Cells

Results and Discussion

Generation of Prom1 = knock-in=20 mice

We replaced the = second exon,=20 which contains the first ATG codon on the Prom1 locus, = with a=20 floxed-lacZ and DTA=20 (Prom1^lacZ,DTA/+) [17], [18] (Figure 1A and 1B

)=20 and generated Prom1^lacZ,DTA/+ mice that = develop=20 normally and are fertile. We also obtained adult=20 Prom1^{lacZ,DTA/lacZ,DTA} mice as reported by = another=20 Prom1 knock-in allele [12] and found that they are also = viable and=20 develop normally, indicating that Prom1 is not essential for = development=20 and our transgene is not toxic.

Prom1 expression in = embryonic=20 and adult central nervous system

Whole-mount X-gal = staining revealed=20 widespread =CE=B2-galactosidase (=CE=B2-gal) activity in the = developing central=20 nervous system where NSCs exist in abundance (Figure 1C

).=20 We detected =CE=B2-gal activity in the ventricular zone (VZ) of = E9.5 embryos to=20 neonatal mice, confirming that Prom1 is expressed in NSCs = in the=20 developing brains (Figure S1). Although = immunoreactivity of Prom1=20 antibody was detected only in the VZ in the adult brain (Figure S2) [19], we found =CE=B2-gal = activity in the=20 cerebellum, midbrain, olfactory bulb, hippocampus, and = telencephalon as=20 well (Figure 1D

=20 and S2). One possible explanation for the difference observed = between our=20 findings and previous findings is that the commercially available=20 anti-Prom1 antibodies recognize limited numbers of Prom1 splicing=20 variants, such as Prom1-s1 [20], whereas the expression of = all of the=20 splice variants may be sensitively detected in our knock-in = mice.

Detailed analyses = revealed that Prom1=20 is expressed in the granular layer of the cerebellum, where the=20 interneurons exist, and in the glomeruli of the olfactory bulb, = which are=20 composed of axons of olfactory cells and dendrites of olfactory = bulb=20 interneurons. (Figure 1D

).=20 We also found that 69% of =CE=B2-gal-positive cells are labeled = for S100=CE=B2 in=20 the hippocampus where NSCs exist in the dentate gyrus (Figure 1D

=20 and 2A=E2=80=932C

).=20 In VZ of lateral ventricle, 90% and 9.5% of =CE=B2-gal-positive = cells are=20 labeled for S100=CE=B2 (ependymal cells, Figure = 2D=E2=80=932F

)=20 and GFAP (SVZ astrocytes, Figure 2Q

),=20 respectively. We also found that 7.9% of GFAP-positive SVZ = astrocytes are=20 positive for Prom1 (Figure 2Q and 2R

),=20 consistent with the past finding that Prom1 is expressed in = multipotent=20 SVZ astrocytes in the adult brain [21]. In the corpus callosum, = the =CE=B2-gal=20 activity was detected in S100=CE=B2-positive astrocytes and = GST=CF=80-positive=20 oligodendrocytes, but not in NeuN-positive neurons, NG2-positive=20 oligodendrocyte precursor cells, or GFAP-positive astrocytes (Figure = 2G=E2=80=932P

).=20 We found similar tendencies in other white matter, neocortex and = midbrain=20 as shown in Figure 2P

.=20 Thus, these data revealed that Prom1 is expressed in various types = of=20 differentiated neural cells as well as NSCs in the adult = brain.

Figure=20 1

Generation of=20 Prom1 knock-in mice and reporter analysis in the = central=20 nervous system.

Genetic ablation of=20 Prom1-expressing cells by inducible Cre recombinase = in=20 vivo

To eliminate=20 Prom1-expressing cells conditionally, the=20 Prom1^lacZ,DTA/+ mice were then crossed with = the=20 CAGG-CreER^TM transgenic mice that ubiquitously = express=20 a tamoxifen-inducible Cre recombinase [22] and generated=20 Prom1^lacZ,DTA/+;CreER^TM = double=20 heterozygotes. Upon the activation of Cre recombinase, the=20 floxed-lacZ cassette is cut off, leading to the specific=20 elimination of the Prom1-expressing cells by DTA induced = upon the=20 activation of Prom1 promoter (Figure 3A

).=20 We first examined whether this experimental system works in = vivo.=20 As expected, after five consecutive days of intraperitoneal = injections of=20 tamoxifen, we induced a number of TUNEL-positive cells in the = granular=20 layer of cerebellum, cortex of telencephalon, white matter, and = midbrain=20 (Figure 3B, 3C

=20 and not shown). In addition, tamoxifen-injected mice lost body = weight and=20 showed a walking abnormality caused by functional defects of the=20 cerebellum. They did, however, survive at least 15 days after the = final=20 injection (Figure S3A). It will be of interest = to further=20 investigate how the elimination of Prom1-expressing cells = causes=20 body weight loss in mice. Nonetheless, we could not eliminate=20 Prom1-expressing cells in VZ of the mice and detected = migrating=20 neuroblasts in the rostral migratory stream (Figure S3B, arrow) and olfactory = bulb,=20 suggesting that neurogenesis was taking place in the mice (Figure S3B). These data indicate = that our=20 experimental system works as expected, although the efficiency of = DTA=20 induction is dependent on the region or cell types.

Figure=20 2

Prom1 is = expressed=20 in mature glial cells and SVZ astrocytes in the adult mouse=20 brain.

Establishment of a mouse model = for=20 GBM

To verify whether=20 Prom1-expressing cells are essential for tumorigenesis, = we=20 adopted a GIC transplantation method into nude mice rather than = tumor=20 induction in the=20 Prom1^lacZ,DTA/+;CreER^TM = mice=20 because the DTA induction efficiency is low in the brain as = mentioned=20 above (Figure S3B). To generate a mouse GIC = line, we=20 first transfected NSCs from=20 Prom1^lacZ,DTA/+;CreER^TM = line with=20 pBabe-Puro-SV40LT vector, which blocks both p53 and Rb pathways, = as high=20 frequencies of mutations in p53 (87%) and Rb (78%) pathways are = seen in=20 human GBM [23], [24]. Then the SV40LT-expressing = NSCs were=20 transfected with pCMS-EGFP-H-Ras^L61 vector, as an = increased=20 activation of the Ras signaling pathway is detected in about 90% = of human=20 GBM [25], to establish=20 = GIC-Prom1^lacZ,DTA/+;CreER^TM line = (GIC-LD). GICs-LD proliferated faster than their parental NSCs as=20 confirmed by the BrdU incorporation assay (Figure 4A

).=20 We also found that when both types of cells were cultured under=20 differentiation conditions, GICs-LD did not show any signs of = undergoing=20 differentiation, while their parental cells were labeled for the = neuronal=20 marker Tuj1, glial markers O4 and glial fibrillary acidic protein = (GFAP),=20 and NSC markers Nestin and Sox2 (not shown) (Figure 4B

).=20 Moreover, GICs-LD formed colonies in soft agar whereas their = parental=20 cells did not (Figure 4C

).=20 Together, these data suggest that GICs-LD are transformed and do = not=20 readily differentiate in vitro.

Figure=20 3

Tamoxifen-dependent=20 Cre activation induces apoptosis of = Prom1-expressing cells=20 in vivo.

We then addressed whether GICs-LD = form tumors=20 in vivo. We injected 10⁴ cells into brains of = nude=20 mice and found that they formed tumors with histological features = similar=20 to human GBM, including hypercellularity, pleomorphism, = multinuclear giant=20 cells, mitosis, and necrosis [26] (Figure 4D

).=20 In addition, we noticed that the tumors were comprised of = Nestin-positive=20 cell populations, rather than a mixture of NSC marker- and = differentiation=20 marker-positive cells, GFAP+ astrocytes, myelin basic protein = (MBP)+=20 mature oligodendrocytes, and NeuN+ mature neurons, indicating that = the=20 tumor cells maintain characteristics of NSCs and are unlikely to=20 differentiate in vivo (Figure 4D

).=20 We also confirmed these results by immunolabeling the tumors for = GFP and=20 neural markers (Figure S4).

We found = Prom1-expression in=20 a portion of brain tumors, especially in the peripheral region of = the=20 tumors (Figure 5

),=20 consistent with the previous findings that human GBM contain a = small=20 population of Prom1-positive cells [5]=E2=80=93[6], [14]. To determine whether=20 Prom1-expressing cells reside in the hypoxic region, we=20 immunolabeled different sections with either CD31 for blood = vessels or=20 HIF1=CE=B1 for hypoxia in combination with X-GAL staining. = Although=20 Prom1-expressing cells were not labeled for HIF1=CE=B1, = they were=20 adjacent to the HIF1=CE=B1-positive hypoxic regions (Figure S5). In contrast,=20 Prom1-expressing cells were not detected around or near = blood=20 vessels (Figure S5). Thus, these data suggest = that=20 Prom1 expression may be regulated by a = HIF1=CE=B1-independent hypoxic=20 signal pathway.

Figure=20 4

Characteristics of=20 the GICs-LD.

The GIC population lacking=20 Prom1-expressing cells can form tumor-spheres in=20 vitro

We also found that = very few=20 GICs-LD were LacZ-positive when cultured as monolayers, whereas a=20 significant number of these cells expressed LacZ when they formed = spheres,=20 suggesting that the Prom1 promoter is activated by cell adhesion = and=20 cell-to-cell communication (Figure 6A

).=20 To test whether the Prom1-expressing cancer cells are = essential=20 for tumorigenesis in this system, we generated=20 GICs-Prom1^DTA/+;CreER^TM = (GICs-DTA)=20 by culturing GICs-LD as a monolayer with 4-hydroxy-tamoxifen, and = then=20 established two independent GICs-DTA sublines using limiting = dilution=20 methods. The genotype of the sublines was confirmed with genomic = PCR=20 analysis (not shown). As shown by Tabu et al [27], we confirmed that when the=20 Prom1 promoter was activated by a histone deacetylase = inhibitor,=20 valproic acid (VPA, 10 mM), over 90% of the cells in GICs-DTA = sublines=20 died within 2 days, while over 60% of their parental GICs-LD lines = survived under the same conditions (Figure = 6A=E2=80=936C

).=20 It was believed that Prom1-positive cells are required for the = formation=20 of tumor-spheres in vitro [8]=E2=80=93[9], [14], however, we found that = GICs-DTA=20 sublines can proliferate and form spheres with no observable = defects (Figure 6D

),=20 indicating that Prom1-expressing cells are not essential = for the=20 maintenance of GIC population in culture.

Figure=20 5

Prom1 is = expressed=20 in the periphery of brain tumors.

GBM formation from the cell = population=20 depleted of Prom1-expressing cells

GICs-DTA sublines were = then=20 transplanted into the brains of nude mice. Both sublines produced = brain=20 tumors with similar characteristics to their control tumors (Figure 4D

=20 and and7A)7A

)=20 and human GBM [26], and led to the death all = of the=20 mice like their parental GICs-LD (n

=3D

4 for each cell lines, P

=3D

0.65) (Figure 7B

).=20 We could not detect LacZ-positive cells in the tumors, confirming = that=20 tumors derived from GICs-DTA sublines do not have any=20 Prom1-expressing cells (not shown). Furthermore, we = performed=20 serial transplantation experiments, and found that all of the mice = (n=3D

3) that received secondary transplantation developed = brain tumors=20 that were phenocopies of primary ones (data not shown) and died = within 30=20 days (Figure 7C

),=20 indicating that GIC-DTA sublines have high capacity for = self-renewal.=20 Taken together, these data reveal that Prom1-expressing = cancer=20 cells are not essential for tumorigenesis and its maintenance in = this GBM=20 model.

Figure=20 6 Prom1-expressing=20 cells are dispensable for maintaining GICs in = culture.

Using the Prom1 = knock-in=20 allele, we demonstrated that Prom1 is predominantly = expressed in=20 differentiated cells as well as NSCs in the adult brain and that = mouse GIC=20 populations that eliminate Prom1-expressing cells can = proliferate=20 in culture and form transplantable GBM in vivo, = suggesting that=20 Prom1 is not a specific marker for NSCs or GICs. However, we = cannot=20 exclude the possibility that Prom1-positive glial cells may behave = as=20 multipotent NSCs as shown previously [19], [28] and that Prom1-positive GICs = may be=20 more malignant than other GICs and are essential for tumorigenesis = in=20 other glioma models. It also remains to be evaluated whether human = GIC=20 population depleting Prom1-expressing cells can form = malignant=20 glioma in vivo. Using the = Prom1^lacZ,DTA/+=20 mice, it is important to clarify whether Prom1-expressing = cells=20 are essential for the tumorigenesis of other cancers, including = breast,=20 intestinal, and prostate cancers. Thus our=20 Prom1^lacZ,DTA/+ mice will be a useful tool for = the=20 research community to examine the functions of = Prom1-expressing=20 cells, which exist throughout the adult body, by crossing them = with other=20 transgenic mice that express inducible and tissue-specific Cre=20 recombinase.

	Figure=20 7 Prom1-expressing=20 cells are not required for the tumorigenesis of GICs in nude = mice.
Top Abstract Introduction Results=20 and Discussion "=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif">= Materials=20 and Methods Supporting=20 Information References	Materials and Methods Mice and Chemicals Prom1 knock-in = mice (Acc.=20 No. CDB0623K: http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;auth=3D0by5ObAp_QGXGvKDzaUAuyQnWXphehWxevSZpSQO7&reftype=3Dextlink&a= mp;article-id=3D2729925&issue-id=3D180340&journal-id=3D440&FR= OM=3DArticle%7CBody&TO=3DExternal%7CLink%7CURI&rendering-type=3Dn= ormal&&http://www.cdb.riken.jp/arg/mutant%20mice20list.html)=20 were generated using a knock-in method as described [29]. To prevent leaky expression = of DTA, a=20 double polyA signal was inserted under the lacZ gene = (http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;auth=3D0du7vM5iToV5NqlRxD1YuUNNwzS2vNmMYhSDYQAdn&reftype=3Dextlink&a= mp;article-id=3D2729925&issue-id=3D180340&journal-id=3D440&FR= OM=3DArticle%7CBody&TO=3DExternal%7CLink%7CURI&rendering-type=3Dn= ormal&&http://www.cdb.riken.jp/arg/cassette.html).=20 Prom1 knock-in mice that were backcrossed and maintained = on a=20 C57BL/6 genetic background, were crossed with ACTB-FLPe = mice [30] to delete the neomycin = selection=20 cassette to generate Prom1^lacZ,DTA/+ mice.=20 Prom1^lacZ,DTA/+ mice were further crossed with = CAGG-CreER^TM mice to delete the lacZ = cassette=20 upon Cre activation, generating=20 Prom1^lacZ,DTA/+;CreER^TM = mice.=20 Genotypes of each mouse were confirmed by Southern blot analysis = and PCR.=20 To induce CreER activation, tamoxifen (Sigma), which was dissolved = in=20 sun-flower oil (20 mg/ml), was injected intraperitoneally into = mice (9=20 mg/40 g body weight) for 5 consecutive days. The mice were = dissected and=20 analyzed 10 days after the final injection. All mouse experiments = were=20 performed following the protocols approved by the RIKEN CDB Animal = Care=20 and Use Committee. Chemicals and growth = factors were=20 purchased from Sigma and PeproTech, respectively, except where=20 indicated. Intracranial cell = transplantation into=20 the brain of nude mice Control cells and = transformed cells=20 were suspended in 5 =C2=B5l of culture medium and injected into = brains of 5~8=20 week-old female nude mice that had been anesthetized with 10%=20 pentobarbital. The stereotactic coordinates of the injection site = were 2=20 mm forward from lambda, 2 mm lateral from the sagittal suture, and = 5 mm=20 deep. For serial = transplantation, brain=20 tumors were dissociated enzymatically using the papain = dissociation system=20 (Worthington). GFP-positive transformed cells were purified using = a JSAN=20 flow cytometer (BayBioscience, Japan), suspended in culture = medium, and=20 transplanted into nude mice soon after sorting. Cell culture NSCs were prepared from = embryonic=20 day 17.5 = Prom1^lacZ,DTA/+;CreER^TM=20 mouse telencephalon and cultured in DMEM/F12 (Gibco, BRL) = supplemented=20 with chemicals, bFGF (10 ng/ml), and EGF (10 ng/ml) (NSC medium), = as=20 described previously [31]. For the monolayer culture, = cells were=20 cultured on poly-D-lysine- (PDL, 15 =C2=B5g/ml) and fibronectin- = (1 =C2=B5g/ml,=20 Invitrogen) coated dishes in NSC medium or on non-coated dishes in = NSCs=20 medium with 5% FCS. To induce neural = differentiation,=20 NSCs were cultured on 8-well chamber slides (Nunc) in DMEM with 1% = FCS for=20 one week. Prom1 expression was induced in the cells = cultured with=20 10 mM Valproic acid (VPA) (Calbiochem) for 3 days. BrdU = incorporation=20 assay was performed as described previously [32]. To isolate GICs-DTA = sublines, GICs-LD=20 were cultured with 4-hydroxy-tamoxifen (100 nM) for 4 days. The = single=20 cells were then isolated and cultured in the 96-well dishes to = avoid=20 contamination of non-recombinant cells. Deletion of the = lacZ gene=20 in GICs-DTA sublines was confirmed by PCR analysis (see=20 below). Southern blot analysis and=20 genotyping To determine the genome = structure of=20 Prom1 knock-in mice, genomic DNA was digested with = XmnI=20 or BamHI. Digoxigenin (DIG)-labeled external or internal = probes=20 were generated using PCR DIG Probe Synthesis kit (Roche). Detailed = probe=20 sequences will be disclosed on request. Hybridization was = conducted using=20 standard protocols. In addition to the external probes (probe A), = internal=20 probes (probe B) were used to detect random integrations of the = targeting=20 vector on the genome. Genotyping of the knock-in mice = was done by=20 PCR. Genomic DNA was isolated from the mouse tail by standard = methods and=20 then used for PCR. The following oligonucleotide DNA primers were=20 synthesized: For Prom1 knock-in allele, prom1-fwd: 5=E2=80=B2-GCT TGAGAGATCAGG = CCAACAAC-3=E2=80=B2,=20 prom1-rvs: 5=E2=80=B2-CTAGAGGGAAGTCATTCGGCTG-3=E2=80=B2 and lacZas:=20 5=E2=80=B2-CGCGTAAAAATGCGCTCAGG-3=E2=80=B2. The=20 primers for CAGG-CreER^TM and = ACTB-FLPe were=20 as described previously [22], [30]. Dimethylsulfoxide (DMSO, = 5%) was=20 added to the all reaction mixture. Cycle parameters were 20 sec at = 94=C2=B0C,=20 30 sec at 60=C2=B0C, and 40 sec at 72=C2=B0C for 35 cycles. RT-PCR was carried out as = described=20 previously [32]. For gapdh, cycle = parameters=20 were 10 sec at 94=C2=B0C, 20 sec at 58=C2=B0C, and 40 sec at = 72=C2=B0C for 25 cycles. DNA=20 primers for Prom1 were synthesized: the 5=E2=80=B2 primer = was 5=E2=80=B2-AGGCTACTTTGAACATTATCTGCA-3=E2=80=B2 and the=20 3=E2=80=B2 primer was 5=E2=80=B2-GGCTTGTCATAACAGGATTGT-3=E2=80=B2. Cycle=20 parameters were 10 sec at 94=C2=B0C, 20 sec at 58=C2=B0C, and 40 = sec at 72=C2=B0C for 40=20 cycles. Immunochemistry Immunostaining was = carried out=20 as described previously [32], [33]. The following antibodies = were used=20 to detect antigens: rat anti-Prom1 (1100; eBioscience), mouse anti-BrdU (11000; Hybridoma Bank), rabbit anti-GFAP (1500; DakoCytomation), mouse anti-Nestin (1500; BD Pharmingen), mouse anti-beta tubulin isotype = III (Tuj1;=20 1200; Sigma), mouse anti-O4 (15; hybridoma supernatant; ATCC), mouse anti-MBP (11000; COVANCE), mouse anti-NeuN (1200; Chemicon), rabbit anti-GFP (1500; Abcam), rat anti-GFP (1500; Nacalai Tesque, Japan), chicken anti-=CE=B2-gal = (1500; Abcam), rabbit anti-NG2 (1200; Chemicon), rabbit anti-S100=CE=B2 (1500; DakoCytomation), mouse anti-GST=CF=80 (1100; BD Pharmingen), mouse anti-PSA-NCAM (1500; gift from T. Seki, Juntendo University School of = Medicine),=20 mouse anti-HIF1=CE=B1 (1500; Abcam) and rabbit anti-CD31 (150; Abcam). The antibodies were detected with goat = anti-rabbit=20 IgG-A488, goat anti-mouse IgG-A488 (1400; Invitrogen), goat anti-mouse IgG-Cy3, donkey = anti-rabbit=20 IgG-Cy3, donkey anti-mouse IgG-Cy3, donkey anti-chicken IgY-Cy3, = donkey=20 anti-rabbit IgG-Cy5 (1200; Jackson ImmunoResearch), and rabbit anti-mouse = IgM-Texas-Red=20 (1200; Jackson ImmunoResearch). To visualize the nuclei, = the cells=20 were counterstained with DAPI (1 =C2=B5g/ml). Soft agar assay We performed a soft = agar assay=20 to examine whether the cultured cells could proliferate=20 anchorage-independently. The cells were suspended in 0.3% top agar = containing optimum medium and layered onto 0.6% bottom agar made = with the=20 same medium. After the top agar solidified, culture medium was = added and=20 the cells were cultured for 20 days with medium changes every 3=20 days. MTT assay One thousand cells = were=20 cultured in 100 =C2=B5l of culture medium in each well of the = 96-well plates=20 with or without VPA (5 or10 mM) for 2 days. The cells were = cultured in the=20 presence of MTT labeling reagent (Roche) for 4 h and then = incubated=20 overnight at 37=C2=B0C with the solubilization solution (10% SDS = in 0.01 M=20 HCl). The viable cells were quantified on a microplate reader = (Bio-Rad)=20 with the absorption spectrum at 595 nm. Brain fixation and = histopathology The dissected mouse = brains were=20 fixed in 4% paraformaldehyde overnight at 4=C2=B0C. After = fixation, the brains=20 were cryoprotected with 12=E2=80=9318% sucrose in PBS and embedded = in Tissue-Tek=20 OCT compound (Miles, Elkhart, IN). Coronal sections (10 =C2=B5m = thick) were=20 prepared from the cerebral cortex and stained with = hematoxylin-eosin (HE)=20 using a standard technique. For X-gal staining, frozen = sections (10 =C2=B5m=20 thick) were fixed by 0.2% glutaraldehyde in PBS or 4% = paraformaldehyde in=20 PBS for 5 min, washed several times, and stained X-gal staining = solution=20 (2 mg/ml X-gal) for 24 hours. Immunohistochemical = analysis was=20 carried out using the standard ABC method (VECTOR) and = fluorescent-dye=20 conjugated secondary antibodies described above. Primary = antibodies used=20 in this experiment are described above. For Nestin immunostaining, = antigen=20 was retrieved by HistoVT One according to the supplier's = instructions=20 (Nacalai Tesque). After the second antibody treatment, samples = were=20 incubated in peroxidase substrate solution and then counterstained = with=20 hematoxylin. TUNEL assay was carried out as described previously = [33]. Transfection Transfection was = performed=20 using the Nucleofector system, according to the supplier's = instructions=20 (Amaxa). In brief, 2=C3=9710⁶ cells were suspended in = the Mouse NSC=20 Nucleofector Solution (100 =C2=B5l) with 10 =C2=B5g vectors, and = were then=20 transfected using the Nucleofector Device. Transfected cells were = cultured=20 in their optimized medium and selected with puromycin (0.25 = =C2=B5g/ml) and=20 hygromycin (100 =C2=B5g/ml). GFP-positive transfected cells were = then purified=20 using a flow cytometer (JSAN) as previously described [33]. Vector construction Full-length SV40LT = cDNA was=20 amplified from pBS-SVT (Japan Health Sciences Foundation, Tokyo, = Japan)=20 using PCR and Phusion polymerase (FINNZYME, Espoo, Finland), = according to=20 the manufacturer's instructions. Full-length mouse H-Ras = was=20 amplified from mouse NSC cDNA using RT-PCR and Phusion polymerase, = and=20 H-Ras^L61 was made by substituting a leucine = for the=20 glycine at codon 61 by PCR. Amplified cDNA were cloned into a = pDrive=20 vector (QIAGEN). The nucleotide sequences were verified using the = BigDye=20 Terminator Kit version 3.1 (Applied Biosystems) and an ABI = sequencer model=20 3130xl (Applied Biosystems). H-Ras^L61 and = SV40LT cDNA=20 were inserted into pCMS-EGFP vector and pBabe-Puro, resulting in=20 pCMS-EGFP-H-Ras^L61 and pBabe-Puro-SV40LT,=20 respectively. The following oligonucleotide DNA primers were = synthesized:=20 For the full-length mouse H-Ras, the 5=E2=80=B2 primer = was 5=E2=80=B2-TGAATTCGCCACCATGACAGAATACAAGCTTGTGGTG-3=E2=80=B2=20 and the 3=E2=80=B2 primer was 5=E2=80=B2-ACTCGAGTCAGGACAGCACACATTTGCAG-3=E2=80=B2. For=20 H-Ras^L61, the 5=E2=80=B2 primer was 5=E2=80=B2-ACAGCAGGTCTAGAAGAGTATA-3=E2=80=B2 and the = 3=E2=80=B2=20 primer was 5=E2=80=B2-TATACTCTTCTAGACCTGCTGT-3=E2=80=B2. For=20 SV40LT, the 5=E2=80=B2 primer was 5=E2=80=B2-AGAATTCGCCACCATGGATAAAGTTTTAAACAGAGAG-3=E2=80=B2=20 and the 3=E2=80=B2 primer was 5=E2=80=B2-AGTCGACTTATGTTTCAGGTTCAGGGGG-3=E2=80=B2. <= /DIV> Statistical analysis Survival = probability was=20 calculated and plotted by Kaplan-Meier methods. The difference was = analyzed using the logrank test. Comparison of cell growth,=20 differentiation, and X-GAL induction were performed by the = unpaired=20 Student's t-test. Comparison of cell viability and cell = death=20 after VPA treatment was performed two-way ANOVA followed by = Bonferroni=20 posttests. All statistic analysis was performed using software = GraphPad=20 Prism 5.0 (Graphpad Software).
Top Abstract Introduction Results=20 and Discussion Materials=20 and Methods "=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif">= Supporting=20 Information References	Supporting Information Figure S1 Developmental expression pattern = of Prom1.=20 X-gal staining (blue) of frozen sections of E9.5, E12.5, E14.5 and = P0=20 Prom1lacZ,DTA/+ mouse brains. Sections were counterstained with = eosin=20 (red) to visualize cytoplasm. Scale, 200 =C2=B5m. (4.28 MB TIF) Click=20 here for additional data file.^{(4.0M, = tif)} Figure S2 Prom1 antibody labels = Prom1-expressing cells=20 in VZ but not in the other regions. Brain sections of adult=20 Prom1lacZ,DTA/+ mice were immunolabeled for =CE=B2-gal (red) and = Prom1 (green).=20 LV, lateral ventricle; DG, dentate gyrus; GL, granular layer. All = nuclei=20 were counterstained with DAPI (blue). Scale, 100 =C2=B5m. (2.02 MB TIF) Click=20 here for additional data file.^{(1.9M, = tif)} Figure S3 Tamoxifen injection decreases body = weight of=20 Prom1lacZ,DTA/+;CreERTM mice but does not affect VZ cells and = their=20 neurogenesis. (A) Relative body weight of mice. Tamoxifen was = injected=20 once a day for five consecutive days and body weight were measured = every=20 five days up to fifteen days after final injection. PC-TM,=20 tamoxifen-injected Prom1lacZ,DTA/+;CreERTM mouse; PC-oil, = oil-injected=20 Prom1lacZ,DTA/+;CreERTM mouse; CreER-TM, tamoxifen-injected = CreERTM mouse;=20 Prom1-TM, tamoxifen-injected Prom1lacZ,DTA/+ mouse. (B) Upper = panels show=20 X-gal staining of frozen sections of tamoxifen-injected=20 Prom1lacZ,DTA/+;CreERTM mouse brains. Lower four panels indicate = PSA-NCAM=20 immunostaining (red) in the ventricular zone and olfactory bulbs = in=20 tamoxifen-injected Prom1lacZ,DTA/+;CreERTM mice. Arrows show = migrating=20 neuroblasts in rostral migratory stream. All nuclei were = counterstained=20 with DAPI (blue). LV, lateral ventricle. Scale, 100 =C2=B5m. (2.25 MB TIF) Click=20 here for additional data file.^{(2.1M, = tif)} Figure S4 Brain tumors derived from GICs-LD = were labeled=20 for Nestin but not differentiation markers. Brain sections with = tumors=20 were immunolabeled for GFP (GICs, green) and either neural stem = cell=20 marker (Nestin, red) or differentiation markers, GFAP (astrocytes, = red),=20 MBP (oligodendrocytes, red), NeuN (mature neurons, red) and NG2=20 (oligodendrocytes precursor cells, red). Although most of = GFP-positive=20 cells were NG2-negative, very few double-positive cells were = detected.=20 Scale, 100 =C2=B5m. (5.61 MB TIF) Click=20 here for additional data file.^{(5.3M, = tif)} Figure S5 Prom1-expressing cells were = adjacent to=20 hypoxic regions but not to blood vessel. Frozen sections of brain = tumors=20 were stained with X-gal activity and then immunoelabeled for GFP = (green)=20 and either CD31 (marker for endothelrial cells, red) or HIF1=CE=B1 = (marker for=20 hypoxia, red). Arrow heads indicate CD31-positive cells. Scale, = 100=20 =C2=B5m. (9.60 MB TIF) Click=20 here for additional data file.^{(9.1M,=20 tif)}
	Acknowledgments We thank S. Hayashi for critical = reading and=20 comments on the manuscript; M. Takeichi and T. Miki for = suggestions and=20 comments; H. Enomoto and M. Nagashimada for technical advice on = Southern=20 blotting; Y. Sasai and T. Wataya for technical advice on=20 immunohistochemical analysis; T. Seki for anti-PSA-NCAM antibody; = T. Hide,=20 T. Takezaki and H. Takanaga for histopathology and mouse = genotyping; K.=20 Miwa for the technical advice on flow cytometry; H. Hiraga for = critical=20 reading of the manuscript.
	Footnotes Competing = Interests:=20 The authors have declared that no competing interests=20 exist. Funding: = The=20 Global COE Program =E2=80=9CGlobal Center for Education and = Research in=20 Integrative Membrane Biology=E2=80=9D from the Ministry of = Education, Culture,=20 Sports, Science, and Technology of Japan. The funders had no role = in study=20 design, data collection and analysis, decision to publish, or = preparation=20 of the manuscript.
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