Primitive Neuroectodermal Tumor Cell Lines Research Articles

Identification of amplified genes from SV40 large T antigen-induced rat PNET cell lines by subtractive cDNA analysis and radiation hybrid mapping.

Primitive neuroectodermal tumors (PNETs) such as human medulloblastomas are genetically heterogeneous and therefore poorly understood. In a rat model the SV40 large T antigen was used to induce neoplasms with characteristic features of PNETs. Tumor development requires a latency period of 8-11 months implicating secondary genetic alterations. To identify such secondary alterations we performed comparative analyses of two phenotypically identical PNET-derived cell lines. Indeed, these cell lines displayed distinct high-level amplification sites. Using a combination of subtractive cDNA analysis and radiation hybrid mapping we have now identified genes in the amplicon regions of the two cell lines. Interestingly, one of these genes encodes the rat homolog of a cytosolic branched chain aminotransferase (BCAT(C)) previously shown to be amplified in a mouse teratocarcinoma cell line. We propose that this simple cloning strategy may serve as a powerful tool for the isolation of genes implicated in known chromosomal aberrations in primary tumors and tumor cell lines.

273 poster Signal transduction pathway to radiation-induced apoptosis in radiosensitive human primitive neuroectodermal tumor (PNET) cell line

273 poster Signal transduction pathway to radiation-induced apoptosis in radiosensitive human primitive neuroectodermal tumor (PNET) cell line

Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors.

Primitive neuroectodermal tumors (PNETs) represent the most frequent malignant brain tumors in childhood. The majority of these neoplasms occur in the cerebellum and are classified as medulloblastomas (MB). Most PNETs develop sporadically; however, their incidence is highly elevated in patients carrying germline APC gene mutations. The APC gene encodes a central component of the WNT/wingless developmental signaling pathway. It regulates the levels of cytoplasmic beta-catenin protein that plays a central role in neural development and cell proliferation. We analyzed 87 sporadic PNETs and 10 PNET cell lines for mutations of the APC gene and beta-catenin (CTNNB1) gene using single strand conformational polymorphism (SSCP) and sequencing analysis. We examined the mutation cluster region of APC (codons 1255--1641) for germline variants and somatic mutations. The medulloblastoma cell line MHH-MED-2 carried a Glu1317Gln missense germline variant and a sporadic MB sample showed a somatic Pro1319Leu substitution. Mutational analysis of exon 3 of CTNNB1 uncovered 4 PNETs (4.8%) with somatic missense mutations. These mutations caused amino acid substitutions in 3 of 80 medulloblastomas (Ser33Phe, Ser33Cys and Ser37Cys) and 1 of 4 supratentorial PNETs (Gly34Val). All mutations affected GSK-3 beta phosphorylation sites of the degradation targeting box of beta-catenin and resulted in nuclear beta-catenin protein accumulation. Deletions of CTNNB1 were not detected by PCR amplification with primers spanning exons 1--5. Our data indicate that inappropriate activation of the WNT/wingless signaling pathway by mutations of its components may contribute to the pathogenesis of a subset of PNETs.

Lovastatin induces apoptosis in a primitive neuroectodermal tumor cell line in association with RB down-regulation and loss of the G1 checkpoint.

To develop a new approach to the treatment of primitive neuroectodermal tumors we evaluated the effect of the HMG-CoA reductase inhibitor lovastatin on the Ewing's sarcoma cell line CHP-100. Lovastatin induced neural morphology and markers including neuron-specific enolase and neurofilament protein. The acquisition of neural morphology required new mRNA synthesis, and cDNA microarray analysis confirmed that lovastatin altered the program of gene expression. After morphologic differentiation the cells underwent rapidly progressive apoptosis. In normal development of neuronal progenitors, differentiation signals trigger p21WAF1 accumulation, RB hypophosphorylation, enhanced RB-E2F-1 association, and G1 arrest, and these events have been shown to protect from apoptosis. In contrast, in the Ewing's sarcoma cells lovastatin triggered differentiation without causing cell cycle arrest: p21WAF1 was not induced, RB remained hyperphosphorylated, and RB protein expression and RB-E2F-1 association were markedly downregulated, suggesting that loss of an RB-regulated G1 checkpoint promoted apoptosis. Consistent with this hypothesis, adenoviral p21WAF1 decreased DNA synthesis and partially protected from lovastatin-induced cytotoxicity. The data demonstrate a new model for examining the genetic regulation of cell fate in a neural progenitor tumor and suggest a new approach to the treatment of this neoplasm.

Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor.

Glial cell line derived neurotrophic factor (GDNF) signals through a multicomponent receptor complex consisting of RET receptor tyrosine kinase and a member of GDNF family receptor alpha (GFRalpha). Recently, it was shown that tyrosine 1062 in RET represents a binding site for SHC adaptor proteins and is crucial for both RAS/mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways. In the present study, we characterized how these two pathways diverge from tyrosine 1062, using human neuroblastoma and primitive neuroectodermal tumor cell lines expressing RET at high levels. In response to GDNF stimulation, SHC bound to GAB1 and GRB2 adaptor proteins as well as RET, and SHC and GAB1 were highly phosphorylated on tyrosine. The complex formation consisting of SHC, GAB1 and GRB2 was almost abolished by replacement of tyrosine 1062 in RET with phenylalanine. Tyrosine-phosphorylated GAB1 was also associated with p85 subunit of PI3-K, resulting in PI3-K and AKT activation, whereas SHC-GRB2-SOS complex was responsible for the RAS/ERK signaling pathway. These results suggested that the RAS and PI3-K pathways activated by GDNF bifurcate mainly through SHC bound to tyrosine 1062 in RET. Furthermore, using luciferase reporter-gene assays, we found that the RAS/ERK and PI3-K signaling pathways are important for activation of CREB and NF-kappaB in GDNF-treated cells, respectively. Oncogene (2000) 19, 4469 - 4475.

Neurotrophins and Trk receptors in primitive neuroectodermal tumor cell lines.

Primitive neuroectodermal tumors (PNETs) are thought to be derived from early central nervous system precursors. Therefore, we hypothesized that the neurotrophins (nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3) and their receptors (TrkA, TrkB, and TrkC), which are involved in the proliferation, differentiation, and survival of neuronal cells, might be important in regulating tumor growth. Using ribonucleic acid (RNA) blotting and reverse transcription-polymerase chain reaction analysis, we investigated the expression of these ligands and their receptors in six PNET cell lines (Daoy, PFSK, D283 Med, UW288-1, CHP707m, and D341 Med). Neurotrophin protein levels were measured using enzyme-linked immunosorbent assay procedures. Receptor function was demonstrated by autophosphorylation. Induction of c-Fos expression and effects on cell proliferation were assessed after the addition of exogenous neurotrophin. Three cell lines expressed messenger RNA for all neurotrophins, whereas the other three expressed two of the three neurotrophins. Neurotrophin protein levels were low. All cell lines expressed trkA messenger RNA. Five expressed the amino terminus of trkB, but three of these did not express the carboxyl terminus. All cell lines contained trkC messenger RNA, but the receptor was truncated in two cell lines. No cell line contained message for a receptor containing an insertion in the tyrosine kinase domain. The addition of neurotrophin to PNET cells resulted in phosphorylation of a protein that was immunoprecipitated with an anti-pan-Trk antibody. c-Fos expression and cell growth were increased by preincubation with neurotrophins, but only in the cell lines expressing the relevant full-length receptors. The expression of neurotrophins and neurotrophin receptors by PNET cell lines is variable. The presence of activated Trk receptors in these cell lines may be required for rapid growth, via an autocrine loop mechanism. This will require further investigation.

Chromosomal imbalances and DNA amplifications in SV40 large T antigen-induced primitive neuroectodermal tumor cell lines of the rat.

Comparative genomic in situ hybridization analysis of four cell lines derived from SV40 large T antigen-induced primitive neuroectodermal tumors of the rat revealed non-recurrent chromosomal copy number changes and DNA amplifications at chromosomal bands 2q34, 4q43qter and 15q12qter in cell lines TZ102, TZ103 and TZ107, respectively. Semi-quantitative PCR and western blot analysis demonstrated amplification and over-expression of the rat N-ras proto-oncogene in TZ102. Furthermore, all cell lines displayed aneuploid cell populations and variable chromosome numbers as assessed by flow cytometry and cytogenetics. These findings suggest that DNA amplification as well as genomic instability may contribute to the pathogenesis of SV40 large T antigen-induced primitive neuroectodermal tumors of the rat.

Migratory potential of transplantable neural tumor cell lines.

Experimentally induced primitive neuroectodermal tumor (PNET) cell lines were transplanted into neonatal and adult rat brain and examined neuropathologically for their tumorigenic potential. Both cell lines showed a striking migratory behavior in both neonatal and adult brain. Migration of tumor cells was found in host brain parenchyma, along white matter tracts and associated with CSF pathways. These neural tumor cell lines provide a valuable tool for the development of strategies against strongly migrating neural tumors.

Bone morphogenetic proteins‐2 and ‐4 attenuate apoptosis in a cerebellar primitive neuroectodermal tumor cell line

Similarities between primitive neuroectodermal tumors and central nervous system (CNS) progenitor cells have evoked interest in the response of these tumors to endogenous growth factors. The bone morphogenetic proteins (BMPs) have recently been found to regulate survival and differentiation of CNS progenitor cell populations. In this study, we investigated the effects of BMP-2, BMP-4, and BMP-6 on the undifferentiated cerebellar primitive neuroectodermal tumor or medulloblastoma cell line DAOY. Analysis by reverse transcriptase-polymerase chain reaction showed that mRNAs for type IA and type II BMP receptors were present in control cultures. In cultures treated with BMP-2, mRNAs for BMP receptor type IB and the activin R-I receptor became evident. Cultures were analyzed for total cell counts, proliferating cell nuclear antigen (PCNA), and apoptotic DNA fragmentation. There was a significant increase in total cell number in the BMP-2 and BMP-4 treatment groups, without any change in PCNA reactivity, and a dramatic decrease in the proportion of apoptotic nuclei at concentrations of BMP-2 and BMP-4 above 5 ng/ml (P < 0.001). These effects were not observed with BMP-6, TGF-β1 or GDNF. These results suggest that the increase in total cell number is due to the attenuation of apoptosis by BMP-2 and BMP-4. The anti-apoptotic effect of BMP-2 and BMP-4 on this neuroectodermal cell line has potential clinical implications for neuroectodermal tumors. J. Neurosci. Res. 56:248–258, 1999. © 1999 Wiley-Liss, Inc.

Vasoactive intestinal peptide (VIP) and VIP receptors: gene expression and growth modulation in medulloblastoma and other central primitive neuroectodermal tumors of childhood.

Vasoactive intestinal peptide (VIP) is a neuromodulator and growth regulator in the developing nervous system. We analyzed 10 primitive neuroectodermal tumor (PNET) cell lines, 29 central PNET (cPNET) and 17 tumors of the Ewing's sarcoma/peripheral PNET family (ESFT) using reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern hybridization. Each of the 10 cell lines and 86.2% of cPNET expressed mRNA for VIP receptor 1 (VIPR1) compared to 52.9% of ESFT. VIPR2 was expressed in 75.8% of cPNET, in 28.6% of ESFT and in all 10 cell lines. cPNET demonstrated high-affinity binding of 125I-VIP on quantitative autoradiography and in competitive binding assays. VIP inhibited tumor cell proliferation in a dose-dependent manner in 5 of 7 PNET cell lines. We conclude that VIPR1 and VIPR2 are highly expressed in cPNET and demonstrate that VIP is a growth modulator in these tumors.

Contrasting levels of p21ras activation and expression of neurofibromin in peripheral primitive neuroectodermal tumour and neuroblastoma cells, and their response to retinoic acid.

Ras protooncogenes encode small guanine nucleotide binding proteins (p21ras) activated by phosphorylation. Phosphorylation of p21ras is predominantly regulated by the GTPase activating proteins type 1 GAP120 and neurofibromin. Increased levels of p21ras-GTP (active) have been associated with increased cell growth and malignant transformation. In this study the relationship between p21ras, type 1 GAP120 and neurofibromin with growth and differentiation has been examined in neuroblastoma and peripheral primitive neuroectodermal tumour (pPNET) cell lines. The level of p21ras protein in neuroblastoma and pPNET cells was the same. However, the amount of p21ras-GTP bound was higher in pPNET than in neuroblastoma cells. This most likely reflects the absence of neurofibromin. Retinoic acid (RA)-induced differentiation and growth inhibition of neuroblastoma cells was associated with an increase in type 1 GAP120 and neurofibromin mRNA, and a decrease in p21ras-GTP. In pPNET cells levels of type 1 GAP120 but not neurofibromin mRNA were increased to similar levels to those in neuroblastoma cells. This was not associated with decreased p21ras-GTP, modulation of growth or change in morphology. In summary, constitutive activation of p21ras may have a role in the biology of pPNET cells. This may reflect abnormalities in neurofibromin expression, and could inpart explain why RA did not induce morphological differentiation and growth inhibition in pPNETs.

Neuroendocrine differentiation in Ewing's sarcomas and primitive neuroectodermal tumors revealed by reverse transcriptase-polymerase chain reaction of chromogranin mRNA.

Ewing's sarcomas (ESs), primitive neuroectodermal tumors (PNETs), and neuroblastomas (NBs) are closely related neoplasms supposedly derived from the neural crest and belonging to the family of the small blue round cell tumors of infancy and childhood. We investigated the expression of the neuroendocrine and neuroectodermal markers chromogranin A (CgA) and secretogranin II (SgII) in ESs, PNETs, and NBs, both in primitive tumors (five, nine, and four cases, respectively) and in established cell lines (three ES and two PNET cell lines). Different technical approaches, namely immunohistochemistry, Northern blot analysis, and reverse transcriptase-polymerase chain reaction (RT-PCR) were used in parallel. Chromogranin A and secretogranin II production was constantly detectable in NBs by all procedures. CgA mRNA was detectable in most ESs and PNETs only by RT-PCR, whereas SgII mRNA was detectable in some ESs and PNETs by Northern blot analysis and in all tumors by RT-PCR. CgA and SgII proteins were never detectable by immunohistochemistry in ESs and PNETs. We conclude that neuroendocrine differentiation is shared by all three tumor entities, being more overt in NBs and rudimentary in ESs and PNETs; traces of chromogranin mRNA are detectable only by a highly sensitive RT-PCR procedure.

P21 (WAF1/Cip1/Sdi1/Pic1) mRNA is expressed in neuroblastoma cell lines but not in Ewing's sarcoma and primitive neuroectodermal tumor cell lines.

The p21 protein inhibits the activity of cyclin-Cdk complexes and suppresses cell cycle progression. Wild type p53 can induce p21, but mutated p53 cannot. Previous studies have demonstrated that mutation of p53 is absent in neuroblastoma (NB). These reports prompted us to examine whether p53 induced p21 in NB. We examined the expression of p21 and p53 mRNA in eight NB, two Ewing's sarcoma (ES) and two primitive neuroectodermal tumor (PNET) cell lines by Northern blot analysis, and sequenced p53 cDNA of these cells. Although p53 mRNA was detected in all analyzed cell lines by Northern blot analysis, p21 mRNA was detected in six NB but not in two NB, two ES and two PNET cell lines. We detected the point mutation of p53 at codon 273 (CGT to TGT) in one NB and two ES cell lines. The non-transforming substitution at codon 72 (CCC to CGC) was detected in all analyzed cell lines. One PNET cell line had a large deletion of p53 cDNA. These results showed that p21 mRNA was usually expressed in NB but not in ES and PNET. This may suggest that the down stream of the p53 signal transduction pathway in NB is different from that of the closely related tumors of ES and PNET.

Two primitive neuroectodermal tumor cell lines require an activated insulin-like growth factor I receptor for growth in vitro.

To determine the expression of the insulin-like growth factors (IGFs) and the IGF-I receptor in primitive neuroectodermal tumor cell lines and to assess the importance of these proteins in the growth of cell lines in vitro. Ribonucleic acid blotting and reverse transcriptase-polymerase chain reaction were used for detection of IGF and IGF-I expression. Ribonucleic acid blotting was used for detection of up-regulation of c-fos in the presence of exogenous growth factor. Immunoprecipitation was used to demonstrate autophosphorylation of the receptor in the presence of exogenous growth factor. Ligand binding analysis was used to determine the binding affinity of the receptor and the number of receptors per cell. Growth of curves in the presence of monoclonal antibody that blocks binding of ligand to receptor was measured to determine the requirement for an activated receptor during growth. Expression of IGF-II was identified in one cell line. No expression of IGF-I was seen in any cell line. Expression of IGF-I receptor was detected in all three cell lines. Immunoprecipitation experiments demonstrated autophosphorylation of the receptor after addition of IGF-I to growing cells. Ligand binding analysis revealed 9.2 x 10(4) and 4 x 10(4) receptors per cell in the Daoy and PFSK cell lines, respectively. Addition of either IGF alone or in combination to serum-starved cells was not able to restore growth of the cell lines. A blocking monoclonal antireceptor antibody decreased growth of Daoy and PFSK cells in a dose-dependent fashion. Complete arrest of growth occurred at 1 microgram/ml antibody in both cell lines. The IGF-I receptor is expressed by primitive neuroectodermal tumor cell lines in vitro. An activated receptor is important for cell proliferation in vitro. Additional work will establish the importance of these findings for tumors in vivo.

Profiles of Neuronal Thread Protein Expression in Alzheimer's Disease

Neuronal thread proteins (NTPs) comprise a family of molecules expressed in brain and primitive neuroectodermal tumor cell lines. In Alzheimer's disease (AD), increased CNS levels of the 21 kD NTP species are correlated with dementia. The present study characterizes the nature and distribution of NTP expression using recently generated brain-derived polyclonal and monoclonal antibodies (MoAbs) to recombinant AD7c-NTP protein. In AD, high levels of NTP immunoreactivity were detected in neuronal perikarya, neuropil fibers, and white matter fibers (axons). In addition, 4 of the 23 AD7c-NTP MoAbs labeled degenerating neurons (with or without neurofibrillary tangles), axonal spheroids, dystrophic neurites, or irregular, wavy threadlike neuropil fibers in AD. Increased neuronal AD7c-NTP immunoreactivity in AD colocalized with perikaryal accumulations of tau-1, phosphorylated neurofilament, and the ganglioside, A2B5. In addition, AD7c-NTP immunoreactivity was detected in early neuritic plaques along with beta-amyloid-containing fibrils, but not in mature plaques, nor was it colocalized in beta A4-immunoreactive fibrils. This study demonstrates the profiles of NTP overexpression in relation to paired helical filament-associated neurodegenerative lesions in AD.

Profiles of Neuronal Thread Protein Expression in Alzheimer's Disease

Neuronal thread proteins (NTPs) comprise a family of molecules expressed in brain and primitive neuroectodermal tumor cell lines. In Alzheimer's disease (AD), increased CNS levels of the 21 kD NTP species are correlated with dementia. The present study characterizes the nature and distribution of NTP expression using recently generated brain-derived polyclonal and monoclonal antibodies (MoAbs) to recombinant AD7c-NTP protein. In AD, high levels of NTP immunoreactivity were detected in neuronal perikarya, neuropil fibers, and white matter fibers (axons). In addition, 4 of the 23 AD7c-NTP MoAbs labeled degenerating neurons (with or without neurofibrillary tangles), axonal spheroids, dystrophic neurites, or irregular, wavy threadlike neuropil fibers in AD. Increased neuronal AD7c-NTP immunoreactivity in AD colocalized with perikarya] accumulations of tau-1, phosphorylated neurofilament, and the ganglioside, A2B5. In addition, AD7c-NTP immunoreactivity was detected in early neuritic plaques along with β-amyloid-containing fibrils, but not in mature plaques, nor was it colocalized in βA4-immunoreactive fibrils. This study demonstrates the profiles of NTP overexpression in relation to paired helical filament-associated neurodegenerative lesions in AD.

Insulin-induced differentiation and modulation of neuronal thread protein expression in primitive neuroectodermal tumor cells is linked to phosphorylation of insulin receptor substrate-1.

Neuronal thread proteins (NTPs) are a family of developmentally regulated molecules expressed in central nervous system (CNS) neurons and primitive neuroectodermal tumor (PNET) cell lines. NTP gene expression is modulated with DNA synthesis, neuritic sprouting, and neuronal differentiation. The present study explores the mechanism of insulin modulation of NTP gene expression during neuronal differentiation using PNET cell lines of CNS origin. PNET2 cells underwent neuronal differentiation with neurite outgrowth coupled with transient up-regulation of several species of NTP. In contrast, PNET1 cells failed to differentiate in response to insulin stimulation, although insulin receptors were more abundant than in PNET2 cells. Analysis of the insulin-mediated signal transduction pathway demonstrated that the lack of insulin responsiveness in PNET1 cells was primarily caused by impaired insulin-mediated tyrosyl phosphorylation of the insulin receptor substrate-1 (IRS-1). Correspondingly, the association between phosphatidyl-inositol 3 (PI3) kinase and phosphorylated IRS-1 was reduced in PNET1 compared with PNET2 cells. In contrast, the levels of IRS-1 protein were similar in PNET1 and PNET2 cells, and expression of the insulin receptor beta subunit (Ir beta) and insulin-mediated tyrosyl phosphorylation of the Ir beta were greater in PNET1 than PNET2 cells. The findings suggest that insulin effected neuronal differentiation and modulation of NTP gene expression in PNET cells utilizes a signal transduction cascade that requires tyrosyl phosphorylation of IRS-1.

The Multiple Tumor Suppressor 1/Cyclin-dependent Kinase Inhibitor 2 Gene in Human Central Nervous System Primitive Neuroectodermal Tumor

THE RECENTLY DESCRIBED multiple tumor suppressor 1/cyclin-dependent kinase inhibitor 2 (MTS1/CDKN2) gene, encoding the cyclin-dependent kinase 4 inhibitor p16, is mutated in a wide variety of tumor cell lines, including gliomas. To investigate the possible role of this gene in the genesis of the central nervous system primitive neuroectodermal tumor (PNET), four established PNET cell lines and 18 PNET surgical specimens were studied for deletions and mutations of the MTS1/CDKN2 gene. One of the four cell lines had homozygous deletion of the gene. No mutation in any of the three MTS1/CDKN2 exons was detected in the other three cell lines by single strand conformational polymorphism analysis. Eighteen surgical PNET specimens were studied for allelic and homozygous deletion at chromosome 9p21, the location of the MTS1/CDKN2 gene. No loss of heterozygosity was noted in 11 of the tumors, and no homozygous loss was noted in any tumor. Single strand conformational polymorphism analysis of the entire coding region of the MTS1/CDKN2 gene revealed no mutation within MTS1/CDKN2 in any tumor. Although deletion of MTS1/CDKN2 may occur in some PNET cell lines, neither deletion nor mutation of the gene is found in tumors before culture. The genesis of the human central nervous system PNET does not involve deletion or mutation of the MTS1/CDKN2 gene.

The multiple tumor suppressor 1/cyclin-dependent kinase inhibitor 2 gene in human central nervous system primitive neuroectodermal tumor.

The recently described multiple tumor suppressor 1/cyclin-dependent kinase inhibitor 2 (MTS1/CDKN2) gene, encoding the cyclin-dependent kinase 4 inhibitor p16, is mutated in a wide variety of tumor cell lines, including gliomas. To investigate the possible role of this gene in the genesis of the central nervous system primitive neuroectodermal tumor (PNET), four established PNET cell lines and 18 PNET surgical specimens were studied for deletions and mutations of the MTS1/CDKN2 gene. One of the four cell lines had homozygous deletion of the gene. No mutation in any of the three MTS1/CDKN2 exons was detected in the other three cell lines by single strand conformational polymorphism analysis. Eighteen surgical PNET specimens were studied for allelic and homozygous deletion at chromosome 9p21, the location of the MTS1/CDKN2 gene. No loss of heterozygosity was noted in 11 of the tumors, and no homozygous loss was noted in any tumor. Single strand conformational polymorphism analysis of the entire coding region of the MTS1/CDKN2 gene revealed no mutation within MTS1/CDKN2 in any tumor. Although deletion of MTS1/CDKN2 may occur in some PNET cell lines, neither deletion nor mutation of the gene is found in tumors before culture. The genesis of the human central nervous system PNET does not involve deletion or mutation of the MTS1/CDKN2 gene.

Animal models of medulloblastomas and related primitive neuroectodermal tumors. A review.

Primitive neuroectodermal tumors (PNET) belong to a family of pediatric neoplasms of the central nervous system (CNS) that are composed predominantly of primitive neuroepithelial cells. Among the different CNS PNET, those arising in the posterior fossa (i.e. medulloblastomas) are prototypical of this group of brain tumors. The basic cell biology of PNET is incompletely understood, but recent studies of human PNET biopsies and cell lines derived therefrom demonstrate that neoplastic cells in human PNET recapitulate many of the phenotypic properties of immature CNS neurons or their progenitors. Based on these findings, it has been possible to develop several animal models of human PNET that will enhance efforts to gain fundamental insights into the induction and progression of PNET. In addition, these model systems will enable emerging gene therapies to be targeted specifically for human PNET. Accordingly, this review summarizes current understanding of the cell biology of human PNET, particularly medulloblastomas, and it highlights the most salient features of representative in vivo model systems of human PNET that are relevant to future studies of these tumors.