Allele-specific losses of heterozygosity on chromosomes 1 and 17 revealed by whole genome scan of ethylnitrosourea-induced gliomas of BDIX x BDIV hybrid rats
Explore the source record for details and available documents.
Journal Article↗
Biomedical subjects
R Buslei
Publications and source records attributed to R Buslei.
Expression of the neurotrophin receptor p75NTR in medulloblastomas is correlated with distinct histological and clinical features: evidence for a medulloblastoma subtype derived from the external granule cell layer.
Medulloblastomas (MBs) are primitive neuroectodermal tumors (PNET) of the cerebellum. They represent the most frequent malignant pediatric brain tumors, but their origin still remains unresolved and controversial. MB cells correspond to different stages of neural development and differentiation as illustrated by their expression of neuronal and glial markers. In the present study, we examined the expression pattern of the common low-affinity neurotrophin receptor p75NTR in a series of 167 MBs by immunohistochemistry. While p75NTR was present in only 17% of classic MBs (CMB), we found expression of p75NTR in all desmoplastic (nodular) MBs (DMB) examined, and in 71% of those MBs with a significant desmoplastic component. Furthermore, both desmoplastic histology and p75NTR expression were present preferentially in those tumors of adolescents and adults that are frequently located laterally in the cerebellar hemispheres. In DMBs, p75NTR was expressed predominantly in the proliferative, reticulin-rich areas, which may show coexpression of GFAP. In the pale islands of DMB, p75NTR was expressed only weakly or was absent. The expression pattern showed an inverse relation to that of the synaptic vesicle protein synaptophysin that was predominant in p75NTR negative classic MBs. Since the neurotrophin receptor p75NTR is expressed in cells of the external granule cell layer (EGL) of the fetal cerebellum, our findings suggest that progenitor cells of the EGL are the cellular origin of a distinct subset of MB, namely the desmoplastic variant and MBs with a significant desmoplastic component.
Adult↗
Neural expression profile of alpha-synuclein in developing human cortex.
Alpha-synuclein is a predominantly neuronal presynaptic protein that may play an important role during synaptogenesis and CNS development. In order to elucidate the human developmental expression profile, we used a polyclonal antiserum against the NAC domain of alpha-synuclein. In normal fetal cortex neuroectodermal precursor cells elicited staining in the soma, whereas, in adult cortex, we observed a staining pattern compatible with synaptic function. The same developmental intraneuronal redistribution was found in neurodegenerative disorders, i.e. somatic staining in neuroectodermal precursors in fetal (trisomy 21) and a synaptic pattern in adult (Down's syndrome, Alzheimer's disease) brains. RT-PCR and Western blot analysis revealed expression at all time points studied (4-7.5 months) during human brain development.
Adult↗
Evidence for activation of microglia in patients with psychiatric illnesses.
Activation of microglia/macrophages is a key event in response to pathological changes in the CNS. HLA-DR is a valuable immunohistochemical marker that specifically reacts with activated microglia cells. In order to elucidate a potential role of microgliosis in severe psychiatric illnesses, post-mortem frontal cortex and hippocampus of patients with schizophrenia (n = 14) and affective disorder (n = 6) and control specimens (n = 13) were studied. Additionally Alzheimer's disease cases (n = 8) were included as a human model system with typical neurodegenerative alterations and microglia activation. All patient groups revealed subjects with abundant microglia immunostaining (schizophrenia, three patients; affective disorder, one patient; Alzheimer's disease, four patients) in both gray and white matter. This finding provides evidence for distinct neuropathological changes in brains of patients with schizophrenia and affective disorder. The activation of microglia cells, which represent a major part of the brain immune response, may help to unravel the pathophysiological processes in severe psychiatric illnesses.
Aged↗
Allele-specific losses of heterozygosity on chromosomes 1 and 17 revealed by whole genome scan of ethylnitrosourea-induced BDIX x BDIV hybrid rat gliomas.
The induction of neural tumors by N-ethyl-N-nitrosourea (EtNU) in inbred strains of rats has evolved as a valuable model system of developmental stage- and cell type-dependent oncogenesis. Tumor yield and latency times are strongly influenced by genetic background. Compared with BDIX rats, BDIV rats are relatively resistant to the induction of brain tumors by EtNU, with a lower tumor incidence and latency periods prolonged by a factor of 3. To characterize genetic abnormalities associated with impaired tumor suppressor gene function in neuro-oncogenesis, losses of heterozygosity (LOHs) and microsatellite instability (MI) were investigated in brain tumors induced by EtNU in (BDIV x BDIX) F(1) and F(2) rats. The polymerase chain reaction was used to amplify 55 polymorphic microsatellite markers spanning the entire rat genome. The tumors displayed different histologies and grades of malignancy, corresponding to part of the spectrum of human gliomas. MI was not observed in any of the tumors. LOH of rat chromosome 1q was predominantly detected in oligodendrogliomas and mixed gliomas, with a 30% incidence in informative cases. 11p15.5, the human genome region syntenic to the consensus region of LOHs observed on rat chromosome 1, has been shown to be involved in the formation of gliomas in humans. Furthermore, rat brain tumors of different histologies often showed allelic imbalances on chromosome 17p. In both cases of LOH, there was a clear bias in favor of the parental BDIV allele, suggesting the involvement of tumor suppressor genes functionally polymorphic between the two rat strains.
Alleles↗
Prominent expression of presenilin-1 in senile plaques and reactive astrocytes in Alzheimer's disease brain.
Mutations in the presenilin 1 (PS-1) gene account for most cases of autosomal dominant early-onset familial Alzheimer's disease (AD). In order to elucidate the cellular expression profile of PS-1 we used a novel N-terminal monoclonal antibody against human PS-1. Immunohistochemical staining was observed strongly in senile plaques, and reactive astrocytes of gray and white matter. Neuronal immunoreactivity, however, was found to be only moderate. RT-PCR analysis of PS-1 mRNA revealed expression throughout human development as well as in human glioma cell lines. Altered PS-1 function may contribute to plaque formation in AD.
Aged↗
Neural antigens in oligodendrogliomas and dysembryoplastic neuroepithelial tumors.
Oligodendrogliomas and dysembryoplastic neuroepithelial tumors (DNT) are frequently associated with epilepsies and share the presence of oligodendroglia-like cells with small round nuclei and optically empty perinuclear halos. The two entities may be difficult to discriminate in small surgical specimens and the origin and differentiation of the oligodendroglia-like cells has been controversial. To better characterize and distinguish the two entities we examined 25 oligodendrogliomas and 16 DNT immunohistochemically for the presence of the proliferation-associated Ki-67 antigen and the following neural antigens: the alpha 1 subunit of the GABAA receptor (GABAR), N-methyl-D-aspartate receptor subunit 1 (NR1), glutamate decarboxylase, neuronal nuclei antigen (NeuN), the embryonal form of the neural cell adhesion molecule (E-NCAM), synaptophysin, neurofilament protein (NFP), and glial fibrillary acidic protein (GFAP). Labeling indices for the Ki-67 antigens were generally less than 1% in both entities. In oligodendrogliomas, more than 50% of the tumors contained NR1- or E-NCAM-positive oligodendroglia-like cells, whereas NeuN-positive tumor cells were never observed. In DNT, NeuN- and NR1-positive tumor cells were present in 44% of the cases each; E-NCAM positivity was less frequent (19%). In both entities, immunoreactivity of oligodendroglia-like cells for GABAR and glutamate decarboxylase was rare and positivity for synaptophysin and neurofilament protein was absent. Some GFAP-positive tumor cells were present in approximately 70% of the cases in both entities. Except for the striking difference in NeuN positivity, the immunohistochemical profiles of oligodendroglia-like cells in DNT and oligodendrogliomas largely overlap and the differential diagnosis continues to rest mainly on conventional histopathological features. The NR1 positivity and the recently reported generation of action potentials in oligodendroglioma cells are consistent with neuronal differentiation and may contribute to the high epileptogenic potential of oligodendrogliomas.
Adult↗
NeuN: a useful neuronal marker for diagnostic histopathology.
The monoclonal antibody A60 specifically recognizes the DNA-binding, neuron-specific protein NeuN, which is present in most neuronal cell types of vertebrates. In this study we demonstrate the potential use of NeuN as a diagnostic neuronal marker using a wide range of formalin-fixed, paraffin-embedded human surgical and autopsy specimens from the central and peripheral nervous system. After microwave antigen retrieval, almost all neuronal populations revealed strong immunoreactivity for NeuN in nuclei, perikarya, and some proximal neuronal processes, whereas more distal axon cylinders and dendritic ramifications were not stained. The stain greatly enhanced the gray matter architecture. NeuN immunoreactivity was not detected in Purkinje cells, most neurons of the internal nuclear layer of the retina, and in sympathetic chain ganglia. We examined nine gangliogliomas and 14 dysembryoplastic neuroepithelial tumors, one ganglioneuroma, and one dysplastic cerebellar gangliocytoma. The neuronal component of all of these lesions showed marked immunoreactivity for NeuN. In addition, NeuN immunoreactivity was focally seen in one of seven medulloblastomas with prominent neuronal differentiation. There was no staining of non-neuronal structures. The results indicate that NeuN immunoreactivity is a sensitive and specific neuronal marker in formalin-fixed, paraffin-embedded tissues, and may be useful in diagnostic histopathology.
Animals↗