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Thesubventricular zone (SVZ) is a region situated on the outside wall of eachlateral ventricle of thevertebrate brain.^[2] It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone containing neuralprogenitor cells, which divide to produceneurons in the process ofneurogenesis.^[3] The primary neuralstem cells of the brain and spinal cord, termedradial glial cells, instead reside in theventricular zone (VZ) (so-called because the VZ lines the inside of the developingventricles).^[4]

In the developingcerebral cortex, which resides in the dorsaltelencephalon, the SVZ and VZ are transient tissues that do not exist in the adult.^[4] However, the SVZ of the ventral telencephalon persists throughout life. The adult SVZ is composed of four distinct layers^[5] of variable thickness and cell density as well as cellular composition. Along with thedentate gyrus of thehippocampus, the SVZ is one of two places whereneurogenesis has been found to occur in the adult mammalian brain.^[6] Adult SVZ neurogenesis takes the form ofneuroblast precursors ofinterneurons that migrate to theolfactory bulb through therostral migratory stream. The SVZ also appears to be involved in the generation ofastrocytes following a brain injury.^[7]

The innermost layer (Layer I) contains a single layer (monolayer) ofependymal cells lining the ventricular cavity; these cells possess apical cilia and several basal expansions that may stand in either parallel or perpendicular to the ventricular surface. These expansions may interact intimately with theastrocytic processes that are interconnected with the hypocellular layer (Layer II).^[5]

The secondary layer (Layer II) provides for a hypocellular gap abutting the former and has been shown to contain a network of functionally correlated Glial Fibrillary Acid Protein (GFAP)-positive astrocytic processes that are linked to junctional complexes, yet lack cell bodies except for the rare neuronal somata. While the function of this layer is yet unknown in humans, it has been hypothesized that theastrocytic andependymal interconnections of Layer I and II may act to regulate neuronal functions, establish metabolichomeostasis, and/or control neuronal stem cellproliferation anddifferentiation during development. Potentially, such characteristics of the layer may act as a remainder of early developmental life or pathway for cellular migration given similarity to ahomologous layer in bovine SVZ shown to have migratory cells common only to higher order mammals.^[5]

The third layer (Layer III) forms a ribbon ofastrocyte cell bodies that are believed to maintain a subpopulation of astrocytes able to proliferate in vivo and form multipotentneurospheres with self-renewal abilities in vitro. While someoligodendrocytes andependymal cells have been found within the ribbon, they not only serve an unknown function, they are uncommon by comparison to the population ofastrocytes that reside in the layer. Theastrocytes present in Layer III can be divided into three populations throughelectron microscopy, with no unique functions yet recognizable; the first type is a small astrocyte of long, horizontal, tangential projections mostly found in Layer II; the second type is found between Layers II and III as well as within the astrocyte ribbon, characterized by its large size and many organelles; the third type is typically found in the lateral ventricles just above thehippocampus and is similar in size to the second type but contains few organelles.^[5]

The fourth and final layer (Layer IV) serves as a transition zone between Layer III with its ribbon ofastrocytes and the brainparenchyma. It is identified by a high presence ofmyelin in the region.^[5]

Four cell types are described in the SVZ:^[8]

1. Ciliated Ependymal Cells (Type E): are positioned facing the lumen of the ventricle, and function to circulate thecerebrospinal fluid.

2. Proliferating Neuroblasts (Type A): express PSA-NCAM (NCAM1), Tuj1 (TUBB3), and Hu, and migrate in line order to theolfactory bulb

3. Slow Proliferating Cells (Type B): expressNestin andGFAP, and function to ensheathe migrating Type ANeuroblasts^[9]

4. Actively Proliferating Cells or Transit Amplifying Progenitors (Type C): express Nestin, and form clusters interspaced among chains throughout region^[10]

The SVZ is a known site ofneurogenesis and self-renewingneurons in the adultbrain,^[11] serving as such due to the interacting cell types, extracellular molecules, and localizedepigenetic regulation promoting such cellular proliferation. Along with thesubgranular zone of thedentate gyrus, the subventricular zone serves as a source ofneural stem cells (NSCs) in the process of adultneurogenesis. It harbors the largest population of proliferating cells in the adult brain of rodents, monkeys and humans.^[12] In 2010, it was shown that the balance between neuralstem cells and neuralprogenitor cells (NPCs) is maintained by an interaction between theepidermal growth factor receptor signaling pathway and theNotch signaling pathway.^[13]

While it has yet to have been studied in-depth in the human brain, the SVZ function in the rodent brain has been, to a certain extent, examined and defined for its abilities. With such research, it has been found that the dual-functioningastrocyte is the dominant cell in the rodent SVZ; this astrocyte acts as not only a neuronal stem cell, but also as a supporting cell that promotesneurogenesis through interaction with other cells.^[8] This function is also induced bymicroglia andendothelial cells that interact cooperatively with neuronal stem cells to promote neurogenesis in vitro, as well as extracellular matrix components such as tenascin-C (helps define boundaries for interaction) andLewis X (binds growth and signaling factors to neural precursors).^[14] The human SVZ is different, however, from the rodent SVZ in two distinct ways; the first is that the astrocytes of humans are not in close juxtaposition to theependymal layer, rather separated by a layer lacking cell bodies; the second is that the human SVZ lacks chains of migratingneuroblasts seen in rodent SVZ, in turn providing for a lesser number of neuronal cells in the human than the rodent.^[2] For this reason, while rodent SVZ proves as a valuable source of information regarding the SVZ and its structure-to-function relationship, the human model will prove significantly different.

EpigeneticDNA modifications have a central role in regulatinggene expression during differentiation ofneural stem cells. The conversion ofcytosine to5-methylcytosine (5mC) in DNA byDNA methyltransferase DNMT3A appears to be an important type of epigenetic modification occurring in the SVZ.^[15]

In addition, some current theories propose that the SVZ may also serve as a site of proliferation for brain tumor stem cells (BTSCs),^[16] which are similar to neural stem cells in their structure and ability to differentiate intoneurons,astrocytes, andoligodendrocytes. Studies have confirmed that a small population of BTSCs can not only produce tumors, but they can also maintain it through innate self-renewal andmultipotent abilities. While this does not allow for inference that BTSCs arise from neural stem cells, it does raise an interesting question as to the relationship that exists from our own cells to those that can cause so much damage.^{[citation needed]}

There are currently many different aspects of the SVZ being researched by individuals in the public and private sectors. Such research interests range from the role of the SVZ inneurogenesis, directed neuronal migration, to the previously mentionedtumorigenesis, as well as many others. Below there are summaries of the work of three different lab groups focusing primarily on one aspect of the SVZ; these include the role of SVZ in cell replacement after brain injury, simulation of NSC proliferation, and role in various tumorigenic cancers.

In their review, Romankoet al. characterized the impact of acute brain injury on the SVZ. Overall, the authors determined that moderate insults to the SVZ allowed for recovery while more severe injuries caused permanent damage to the region. Additionally, the neural stem cell population within the SVZ is likely responsible for this injury response.^[17]

The effects ofirradiation on the SVZ provided for a recognition of the amount or dose of radiation that can be given is determined mostly by the tolerance of the normal cells near thetumor. As described, the increasing dose of radiation and age led to decrease in three cell types of the SVZ, yet repair capacity of the SVZ was observed despite the lack ofwhite matternecrosis; this occurred likely because the SVZ was able to gradually replace theneuroglia of the brain.Chemotherapeutics were also tested for their effects on the SVZ, as they are currently used for many diseases yet lead to complications within thecentral nervous system. To do so,methotrexate (MTX) was used alone and in combination with radiation to find that roughly 70% of the total nuclear density of the SVZ had been depleted, yet given loss ofneuroblast cells (progenitor cells), it was remarkable to find that SVZ NSCs would still generateneurospheres similar to subjects that did not receive such treatment. In relation to interruption of blood supply to the brain, cerebralhypoxia/ischemia (H/I) was found to also decrease the cell count of the SVZ by 20%, with 50% ofneurons in thestriatum andneocortex being destroyed, but the cell types of the SVZ killed were as non-uniform as the region itself. Upon subsequent testing, it was found that a different portion of each cell was eliminated, yet the medial SVZ cell population remained mostly alive. This may provide for a certain resiliency of such cells, with the uncommitted progenitor cells acting as the proliferating population followingischemia. Mechanical brain injury also induces cell migration and proliferation, as was observed in rodents, and it may also increase cell number, negating the previously held notion that no new neuronal cells can be generated.^{[citation needed]}

In conclusion, this group was able to determine that cells in the SVZ are able to produce newneurons andglia throughout life, given it does not suffer damage as it is sensitive to any deleterious effects. Therefore, the SVZ can recover itself following mild injury, and potentially provide for replacement cell therapy to other affected regions of the brain.^{[citation needed]}

In an attempt to characterize and analyze the mechanism concerning the proliferation of neuronal cells within the subventricular zone, Decressacet al. observed the proliferation of neural precursors in the mouse subventricular zone through injection of theneuropeptide Y (NPY).^[18] NPY is a commonly expressed protein of the central nervous system that has previously been shown to stimulate proliferation of neuronal cells in theolfactoryepithelium andhippocampus. Thepeptide's effects were observed throughBrdU labeling and cellphenotyping that provided evidence for the migration ofneuroblasts through therostral migratory stream to theolfactory bulb (confirming previous experiments) and to thestriatum. Such data supports the author's hypothesis in thatneurogenesis would be stimulated through introduction of such apeptide.^{[citation needed]}

As NPY is a 36amino acidpeptide associated with many physiological and pathological conditions, it has multiplereceptors that are broadly expressed in the developing and mature rodent brain. However, givenin vivo studies performed by this group, the Y1 receptor displayed specifically mediated neuroproliferative effects through the induction of NPY with increased expression in the subventricular zone. Identification of the Y1 receptor also sheds light on the fact that the phenotype of expressed cells from such mitotic events are actually cells that areDCX+ (neuroblasts that migrate directly to thestriatum) type. Along with the effects of NPY injection on striataldopamine,GABA andglutamate parameters to regulateneurogenesis in the subventricular zone (previous study), this finding is still under consideration as it could be a secondary modulator of the aforementionedneurotransmitters.^{[citation needed]}

As is necessary for all research, this group conducted its experiments with a broad perspective on the application of their findings, which they claimed could potentially benefit potential candidates for endogenous brain repair through stimulation of the subventricular zone neural stem cell proliferation. This natural molecular regulation of adult neurogenesis would be adjunct with therapies of appropriate molecules such as the tested NPY and Y1 receptor, in addition topharmacological derivatives, in providing for manageable forms ofneurodegenerative disorders of the striatal area.^{[citation needed]}

In an attempt to characterize the role of the subventricular zone in potentialtumorigenesis, Quinones-Hinojosaet al. found that brain tumor stem cells (BTSCs) arestem cells that can be isolated from brain tumors by similar assays used for neuronal stem cells.^[5] In forming clonal spheres similar toneurospheres of neuronal stem cells, these BTSCs were able to differentiate intoneurons,astrocytes andoligodendrocytesin vitro, yet more importantly capable of initiatingtumors at low cell concentrations, providing a self-renewal capacity. It was therefore proposed that a small population of BTSCs with such self-renewal capabilities were maintainingtumors in diseases such asleukemia andbreast cancer.^{[citation needed]}

Several characterizing factors lead to the proposed idea of neuronal stem cells (NSCs) being the origin for BTSCs, as they share several features. These features are shown in the figure.

This group provides evidence of the SVZ's apparent role intumorigenesis as demonstrated by the possession of mitogenic receptors and their response to mitogenic stimulation, specifically type C cells that express theepidermal growth factor receptor (EGFR), making them highly proliferative and invasive. Additionally, the existence ofmicroglia andendothelial cells within the SVZ was found to enhanceneurogenesis, as well as providing for some directional migration ofneuroblasts from the SVZ.^{[citation needed]}

Recently, the human SVZ has been characterized in brain tumor patients at phenotypic and genetic level. These data reveal that in half of the patients the SVZ is an exact site oftumorigenesis whereas in the remaining patients it represents an infiltrated region.^[19] Thus, it is distinctly possible that in humans a relationship exists between the NSC generation of the region and the consistently self-renewing cells of primary tumors that give way to secondary tumors once removed or irradiated.^{[citation needed]}

While it remains to be definitely proven whether the SVZ stem cells are the cell of origin for brain tumors such as gliomas, there is strong evidence that suggests increased tumor aggressiveness and mortality in those patients whose high-grade gliomas infiltrate or contact the SVZ.^[20][21]

In prostate cancer, tumor-induced neurogenesis is characterized by the recruitment of neural progenitor cells (NPC) from SVZ. NPCs infiltrate the tumor where they differentiate into autonomic neurons (adrenergic neurons mainly) that stimulate tumor growth.^[22]

• Neuroscience

• Developmental neuroscience

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