The Role of NG2 Proteoglycan in Glioma

Neuron glia antigen-2 ((NG2), also known as chondroitin sulphate proteoglycan 4, or melanoma-associated chondroitin sulfate proteoglycan) is a type-1 membrane protein expressed by many central nervous system (CNS) cells during development and differentiation and plays a critical role in proliferation and angiogenesis. ‘NG2’ often references either the protein itself or the highly proliferative and undifferentiated glial cells expressing high levels of NG2 protein. NG2 glia represent the fourth major type of neuroglia in the mammalian nervous system and are classified as oligodendrocyte progenitor cells by virtue of their committed oligodendrocyte generation in developing and adult brain. Here, we discuss NG2 glial cells as well as NG2 protein and its expression and role with regards to CNS neoplasms as well as its potential as a therapeutic target for treating childhood CNS cancers.     

Cancer stem cells in the mammalian central nervous system

Malignant tumours intrinsic to the central nervous system (CNS) are among the most difficult of neoplasms to treat effectively. The major biological features of these tumours that preclude successful therapy include their cellular heterogeneity, which renders them highly resistant to both chemotherapy and radiotherapy, and the propensity of the component tumour cells to invade, diffusely, the contiguous nervous tissues. The tumours are classified according to perceived cell of origin, gliomas being the most common generic group. In the 1970s transplacental administration of the potent neurocarcinogen, N-ethyl-N-nitrosourea (ENU), enabled investigation of the sequential development of brain and spinal neoplasms by electron microscopy and immunohistochemistry. The significance of the primitive cells of the subependymal plate in cellular origin and evolution of a variety of glial tumours was thereby established. Since then, the development of new cell culture methods, including the in vitro growth of neurospheres and multicellular tumour spheroids, and new antigenic markers of stem cells and glial/neuronal cell precursor cells, including nestin, Mushashi-1 and CD133, have led to a reappraisal of the histological classification and origins of CNS tumours. Moreover, neural stem cells may also provide new vectors in exciting novel therapeutic strategies for these tumours. In addition to the gliomas, stem cells may have been identified in paediatric tumours including cerebellar medulloblastoma, thought to be of external granule cell neuronal derivation. Interestingly, while the stem cell marker CD133 is expressed in these primitive neuroectodermal tumours (PNETs), the chondroitin sulphate proteoglycan neuronal/glial 2 (NG2), which appears to denote increased proliferative, but reduced migratory activity in adult gliomas, is rarely expressed. This is in contrast to the situation in the histologically similar supratentorial PNETs. A possible functional 'switch' between proliferation and migration in developing neural tumour cells may exist between NG2 and ganglioside GD3. The divergent pathways of differentiation of CNS tumours and the possibility of stem cell origin, for some, if not all, such neoplasms remain a matter for debate and continued research, but the presence of self-renewing neural stem cells in the CNS of both children and adults strongly suggests a role for these cells in tumour initiation and resistance to current therapeutic strategies.     

脐带血来源干细胞神经分化的研究进展

中枢神经系统损伤后的自身修复能力有限,因而研究者致力于寻找一种合适的细胞进行移植以代替受损的神经细胞修复神经损伤。近年来的研究表明,脐带血干细胞能够在体外诱导条件下向神经样细胞分化,并在动物体内实验中促进神经损伤的恢复,有可能作为一种有效的细胞资源,应用于人类中枢神经系统疾病的细胞替代治疗以及神经保护与支持。     

Stem cells in brain tumorigenesis and their impact on therapy

The concept that the genesis of new cells in the adult mammalian brain is negligible has long influenced our perception and understanding of the origin and development of central nervous system (CNS) tumors. The discovery that neurons and glia are produced throughout life from neural stem cells provides new possibilities for candidate precursor cells of CNS neoplasms. The emerging hypothesis is that alterations in the cellular and genetic mechanisms that control adult neurogenesis might contribute to brain tumorigenesis. As such, opportunities become available to identify new therapeutic strategies.     

肾上腺素受体在大鼠中枢神经系统发育中的作用研究

去甲肾上腺素和肾上腺素受体在大鼠中枢神经系统（CNS）的发育早期开始表达,且受体表达的时空模式与脑发育过程中某些脑区神经元的迁移和分化相一致,这提示去甲肾上腺素在中枢神经系统的发育中具有重要作用。本文论述了胚胎和新出生的大鼠不同脑区肾上腺素受体mRNA的表达模式以及这些受体对体外培养的成熟细胞和相应的前体细胞的调控效应,通过离体和在体研究的实验证据,阐述肾上腺素受体介导了去甲肾上腺素对神经前体细胞的增殖、生长、迁移、分化和存活的调控作用。进一步明确了去甲肾上腺素在CNS发育中所起的作用,使其可作为成体脑修复的助动剂而赋予新的意义。     

Induction of differentiation of rat retinal, germinal, neuroepithelial cells by dbcAMP

Little is known about the factors that regulate the production of neurons during the development of the vertebrate central nervous system (CNS); however, evidence from several neuronal cell lines suggests that an increase in intracellular cAMP might trigger the process of differentiation. To determine if a similar process is involved in differentiation during normal CNS neurogenesis, we raised the intracellular level of cAMP in primary cultures of mitotically active, germinal neuroepithelial cells from fetal and postnatal rat retina. This treatment induced differentiation of the CNS precursors, causing the cells to cease DNA synthesis and increase their expression of proteins normally found in differentiated retinal cells. These results indicate that germinal neuroepithelial cell differentiation can be controlled through the cAMP second messenger system, and that the regulation of this system may in part determine the numbers and ratios of the various classes of neurons during the normal development of the CNS.     

Drosophila single-minded gene and the molecular genetics of CNS midline development.

Our goal is to understand the molecular mechanisms that govern the formation of the central nervous system. In particular, we have focused on the development of a small group of neurons and glia that lie along the midline of the Drosophila CNS. These midline cells possess a number of unique attributes which make them particularly amenable to molecular, cellular, and genetic examinations of nervous system formation and function. In addition, the midline cells exhibit distinctive ontogeny, morphology, anatomical position, and patterns of gene expression which suggest that they may provide unique functions to the developing CNS. The single-minded gene encodes a nuclear protein which is specifically expressed in the midline cells and has been shown to play a crucial role in midline cell development and CNS formation. Genetic experiments reveal that sim is required for the expression of many CNS midline genes which are thought to be involved in the proper differentiation of these cells. In order to identify additional genes which are expressed in some or all of the midline cells at different developmental stages, a technique known as enhancer trap screening was employed. This screen led to the identification of a large number of potential genes which exhibit various midline expression patterns and may be involved in discrete aspects of midline cell development. Further molecular, genetic, and biochemical analyses of sim and several of the enhancer trap lines are being pursued. This should permit elucidation of the genetic hierarchy which acts in the specification, differentiation, and function of these CNS midline cells.     

Transplantation of neural stem cells into the spinal cord after injury

Thanks to advances in the stem cell biology of the central nervous system (CNS), the previously inconceivable regeneration of the damaged CNS is approaching reality. The availability of signals to induce the appropriate differentiation of the transplanted and/or endogenous neural stem cells (NSCs) as well as the timing of the transplantation are important for successful functional recovery of the damaged CNS. Because the immediately post-traumatic microenvironment of the spinal cord is in an acute inflammatory stage, it is not favorable for the survival and differentiation of NSC transplants. On the other hand, in the chronic stage after injury, glial scars form in the injured site that inhibit the regeneration of neuronal axons. Thus, we believe that the optimal timing of transplantation is 1-2 weeks after injury.     

Physiological and pathological roles of interleukin-6 in the central nervous system

The cytokine interleukin-6 (IL-6) is an important mediator of inflammatory and immune responses in the periphery. IL-6 is produced in the periphery and acts systemically to induce growth and differentiation of cells in the immune and hematopoietic systems and to induce and coordinate the different elements of the acute-phase response. In addition to these peripheral actions, recent studies indicate that IL-6 is also produced within the central nervous system (CNS) and may play an important role in a variety of CNS functions such as cell-to-cell signaling, coordination of neuroimmune responses, protection of neurons from insult, as well as neuronal differentiation, growth, and survival. IL-6 may also contribute to the etiology of neuropathological disorders. Elevated levels of IL-6 in the CNS are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma, and viral and bacterial meningitis. Moreover, several studies have shown that chronic overexpression of IL-6 in transgenic mice can lead to significant neuroanatomical and neurophysiological changes in the CNS similar to that commonly observed in various neurological diseases. Thus, it appears that IL-6 may play a role in both physiological and pathophysiological processes in the CNS.     

The cytopathology of cerebrospinal fluid. II. Metastatic cancer, meningeal carcinomatosis and primary central nervous system neoplasms

The evaluation of cerebrospinal fluid (CSF) requires adaption of basic cytopathologic principles to the specific neoplasms that involve the central nervous system (CNS). In this review, general criteria for detecting malignant cells in CSF are presented. The incidence and cytologic characteristics of specific metastatic tumors that involve CSF are reviewed, and the incidence, pathogenesis and natural history of meningeal carcinomatosis are discussed. The role of cytopathology in the detection and management of primary CNS tumors is presented. Emphasis is placed on the cytologic characteristics of individual types of primary brain tumors and the application of fine needle aspiration biopsy to intracranial lesions.     

Accuracy of cytologic diagnosis of central nervous system neoplasms in sterotactic biopsies

The cytohistologic correlation is reported for 112 of the 128 consecutive sterotactic aspiration biopsies performed on patients with clinical and neuroradiologic evidence of brain tumors investigated at the Neurosurgery Department, Karolinska Hospital, from 1976 to 1979. The cytodiagnostic accuracy of benign and malignant tumors was 87% when adequate cell material was obtained. In 17 benign tumors of the sellar region, the diagnostic rate was 88%; cytologic examination independent of histologic biopsy is feasible in this area. The cytodiagnostic accuracy for 95 malignant central nervous system (CNS) tumors was 87% after adjusting for the appreciable sampling error inherent in the use of a stereotactic procedure during the early phase of the study. Two histopathologically proven infectious lesions were reported cytologically as benign. The main microscopic problems were the recognition of highly differentiated astroglial neoplasms and the differential diagnosis between poorly differentiated brain neoplasms and metastases to the CNS. Cytodiagnostic accuracy of CNS tumors can be increased by technical improvements in the stereotactic device, diagnostic experience and immunochemical staining.     

Crush preparations of lesions of the central nervous system. A useful adjunct to the frozen section

A series of 32 cases in which crush preparations were used in addition to frozen sections for the rapid diagnosis of lesions of the central nervous system (CNS) is presented. The cytopathologic features in crush preparations of astrocytomas, glioblastomas multiforme and a pituitary adenoma are described. Excellent preservation of cellular detail was seen in the crush preparations. Frozen sections lacked cytologic detail but provided a better view of the tissue architecture. The crush preparations yielded the correct diagnosis in 29 of the 32 cases. In the other three, a secondary component of the neoplasms (oligodendroglioma and fibrosarcoma) was identified only in the paraffin sections. Use of both frozen sections and crush preparations is recommended for all cases in which an immediate diagnosis of a CNS lesion is required.     

Reticulum Cell Sarcoma of the Central Nervous System

One variety of sarcoma of the central nervous system (CNS) has been referred to under such synonyms as perithelial sarcoma, microglioma, and reticulum cell sarcoma. A case of diffuse involvement of the CNS is reported and the author believes that the tumour is a reticulum cell sarcoma because: (1) in addition to involvement of the CNS, lesions characteristic of a diffuse lymphomatous process were present in extraneural sites; (2) silver carbonate impregnation of the tumour cells was demonstrated. This tinctorial property has been reported as characteristic of microgliomas but has been shown to be an unreliable criterion for the differentiation of the cells of microglial from those of reticulum cell sarcomas. It is concluded that in such cases the CNS is the initial and major focus of a multicentric malignant lymphoma which has the histologic characteristics of a reticulum cell sarcoma.     

The developing dorsal ganglion of the salp Thalia democratica,and the nature of the ancestral chordate brain

The development of the dorsal ganglion of the salp, Thalia democratica, is described from electron microscope reconstructions up to the stage of central neuropile formation. The central nervous system (CNS) rudiment is initially tubular with an open central canal. Early developmental events include: (i) the formation of a thick dorsal mantle of neuroblasts from which paired dorsal paraxial neuropiles arise; (ii) the differentiation of clusters of primary motor neurons along the ventral margin of the mantle; and (iii) the development from the latter of a series of peripheral nerves. The dorsal paraxial neuropiles ultimately connect to the large central neuropile, which develops later. Direct contact between neuroblasts and muscle appears to be involved in the development of some anterior nerves. The caudal nerves responsible for innervating more distant targets in the posterior part of the body develop without such contacts, which suggests that a different patterning mechanism may be employed in this part of the neuromuscular system. The results are compared with patterns of brain organization in other chordates. Because the salp CNS is symmetrical and generally less reduced than that of ascidian larvae, it is more easily compared with the CNS of amphioxus and vertebrates. The dorsal paraxial centres in the salp resemble the dorsolateral tectal centres in amphioxus in both position and organization; the central neuropile in salps likewise resembles the translumenal system in amphioxus. The neurons themselves are similar in that many of their neurites appear to be derived from the apical surface instead of the basal surface of the cell. Such neurons, with extensively developed apical neurites, may represent a new cell type that evolved in the earliest chordates in conjunction with the formation of translumenal or intralumenal integrative centres. In comparing the salp ganglion with vertebrates, we suggest that the main core of the ganglion is most like the mes-metencephalic region of the vertebrate brain, i.e. the zone occupied by the midbrain, isthmus, and anterior hindbrain. Counterparts of more anterior regions (forebrain) and posterior ones (segmented hindbrain) appear to be absent in salps, but are found in other tunicates, suggesting that evolution has acted quite differently on the main subdivisions of the CNS in different types of tunicates.     

Kir channels in the CNS: emerging new roles and implications for neurological diseases

Inwardly rectifying potassium (Kir) channels have long been regarded as transmembrane proteins that regulate the membrane potential of neurons and that are responsible for [K(+)] siphoning in glial cells. The subunit diversity within the Kir channel family is growing rapidly and this is reflected in the multitude of roles that Kir channels play in the central nervous system (CNS). Kir channels are known to control cell differentiation, modify CNS hormone secretion, modulate neurotransmitter release in the nigrostriatal system, may act as hypoxia-sensors and regulate cerebral artery dilatation. The increasing availability of genetic mouse models that express inactive Kir channel subunits has opened new insights into their role in developing and adult mammalian tissues and during the course of CNS disorders. New aspects with respect to the role of Kir channels during CNS cell differentiation and neurogenesis are also emerging. Dysfunction of Kir channels in animal models can lead to severe phenotypes ranging from early postnatal death to an increased susceptibility to develop epileptic seizures. In this review, we summarize the in vivo data that demonstrate the role of Kir channels in regulating morphogenetic events, such as the proliferation, differentiation and survival of neurons and glial cells. We describe the way in which the gating of Kir channel subunits plays an important role in polygenic CNS diseases, such as white matter disease, epilepsy and Parkinson's disease.