The subventricular zone (SVZ) is a term used to describe both embryonic and adult neural tissues in the vertebrate central nervous system (CNS). In embryonic life, the SVZ refers to a secondary proliferative zone containing neural progenitor cells, which divide to produce neurons in the process of neurogenesis [1, 2]. The primary neural stem cells of the brain and spinal cord, termed radial glial cells, reside in the ventricular zone (VZ) (so-called because the VZ lines the developing ventricles) . In the developing cerebral cortex, which resides in the dorsal telencephalon, the SVZ and VZ are transient tissues that do not exist in the adult . However, the SVZ of the ventral telencephalon persists throughout life.
The adult SVZ is a paired brain structure situated throughout the lateral walls of the lateral ventricles . It is composed of four distinct layers of variable thickness and cell density, as well as cellular composition. Along with the dentate gyrus of the hippocampus, the SVZ is one of two places where neurogenesis has been found to occur in the adult mammalian brain [5, 6].
The innermost layer (Layer I) contains a single layer (monolayer) of ependymal 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 the astrocytic processes that are interconnected with the hypocellular layer (Layer II) .
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 the astrocytic and ependymal interconnections of Layer I and II may act to regulate neuronal functions, establish metabolic homeostasis, and/or control neuronal stem cell proliferation and differentiation 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 a homologous layer in bovine SVZ shown to have migratory cells common only to higher order mammals 
The third layer (Layer III) forms a ribbon of astrocyte cell bodies that are believed to maintain a subpopulation of astrocytes able to proliferate in vivo and form multipotent neurospheres with self-renewal abilities in vitro. While some oligodendrocytes and ependymal cells have been found within the ribbon, they not only serve an unknown function, they are uncommon by comparison to the population of astrocytes that reside in the layer. The astrocytes present in Layer III can be divided into three populations through electron 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 the hippocampus and is similar in size to the second type but contains few organelles .
The fourth and final layer (Layer IV) serves as a transition zone between Layer III with its ribbon of astrocytes and the brain parenchyma. It is identified by a high presence of myelin in the region .
Four cell types are described in the SVZ:
1. Ciliated Ependymal Cells (Type E): are positioned facing the lumen of the ventricle, and function to circulate the cerebrospinal fluid.
2. Proliferating Neuroblasts (Type A): express PSA-NCAM (NCAM1), Tuj1 (TUBB3), and Hu, and migrate in line order to the Olfactory Bulb
3. Slow Proliferating Cells (Type B): express Nestin and GFAP, and function to ensheathe migrating Type A Neuroblasts
4. Actively Proliferating Cells or Transit Amplifying Progenitors (Type C): express Nestin, and form clusters interspaced among chains throughout region
The SVZ is a known site of neurogenesis and self-renewing neurons in the adult brain, serving as such due to the interacting cell types, extracellular molecules, and localized epigenetic regulation promoting such cellular proliferation. Along with the subgranular zone of dentate gyrus, the subventricular zone serves as a source of neural stem cells(NSCs) in the process of adult neurogenesis. It harbors the largest population of proliferating cells in the adult brain of rodents, monkeys and humans. In 2010, it was shown that the balance between neural stem cells and neural progenitor cells (NPCs) is maintained by an interaction between the epidermal growth factor receptor signaling pathway and the Notch signaling pathway.
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-functioning astrocyte 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 promotes neurogenesis through interaction with other cells. This function is also induced by microglia and endothelial 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) and Lewis X (binds growth and signaling factors to neural precursors). 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 the ependymal layer, rather separated by a layer lacking cell bodies; the second is that the human SVZ lacks chains of migrating neuroblasts seen in rodent SVZ, in turn providing for a lesser number of neuronal cells in the human than the rodent. 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.
In addition, some current theories propose that the SVZ may also serve as a site of proliferation for brain tumor stem cells (BTSCs), which are similar to neural stem cells in their structure and ability to differentiate into neurons, astrocytes, and oligodendrocytes. Studies have confirmed that a small population of BTSCs can not only produce tumors, but they can also maintain it through innate self-renewal and multipotent 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.
The human subventricular zone: A source of new cells and a potential source of brain tumors
In an attempt to characterize the role of the subventricular zone in potential tumorigenesis, Quinones-Hinojosa et al. found that brain tumor stem cells (BTSCs) are stem cells that can be isolated from brain tumors by similar assays used for neuronal stem cells. In forming clonal spheres similar to neurospheres of neuronal stem cells, these BTSCs were able to differentiate into neurons, astrocytes and oligodendrocytes in vitro, yet more importantly capable of initiating tumors 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 maintaining tumors in diseases such as leukemia and breast cancer.
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 in tumorigenesis as demonstrated by the possession of mitogenic receptors and their response to mitogenic stimulation, specifically type C cells that express the epidermal growth factor receptor (EGFR), making them highly proliferative and invasive. Additionally, the existence of microglia and endothelial cells within the SVZ was found to enhance neurogenesis, as well as providing for some directional migration of neuroblasts from the SVZ.
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 of tumorigenesis whereas in the remaining patients it represents an infiltrated region. 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.
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.
This article uses material from the Wikipedia article Subventricular zone, which is released under the Creative Commons Attribution-Share-Alike License 3.0
- Popp A, Urbach A, Witte OW, Frahm C (2009). Reh TA, ed. “Adult and Embryonic GAD Transcripts Are Spatiotemporally Regulated during Postnatal Development in the Rat Brain”. PLoS ONE. 4 (2): e4371. PMC2629816 . PMID 19190758. doi:1371/journal.pone.0004371.
- Noctor, SC; Martínez-Cerdeño, V; Ivic, L; Kriegstein, AR (February 2004). “Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases.”. Nature Neuroscience. 7 (2): 136–44. PMID14703572. doi:1038/nn1172.
- Rakic, P (October 2009). “Evolution of the neocortex: a perspective from developmental biology.”. Nature Reviews. Neuroscience. 10 (10): 724–35. PMC2913577 . PMID 19763105. doi:1038/nrn2719.
- Quiñones-Hinojosa, A; Sanai, N; Soriano-Navarro, M; Gonzalez-Perez, O; Mirzadeh, Z; Gil-Perotin, S; Romero-Rodriguez, R; Berger, MS; Garcia-Verdugo, JM; Alvarez-Buylla, A (Jan 20, 2006). “Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells.”. The Journal of Comparative Neurology. 494 (3): 415–34. PMID16320258. doi:1002/cne.20798.
- Quiñones-Hinojosa, A; Chaichana, K (Jun 2007). “The human subventricular zone: a source of new cells and a potential source of brain tumors.”. Experimental neurology. 205 (2): 313–24. PMID17459377. doi:1016/j.expneurol.2007.03.016.
- Ming, GL; Song, H (May 26, 2011). “Adult neurogenesis in the mammalian brain: significant answers and significant questions.”. Neuron. 70 (4): 687–702. PMC3106107 . PMID 21609825. doi:1016/j.neuron.2011.05.001.
- Doetsch, F; García-Verdugo, JM; Alvarez-Buylla, A (Jul 1, 1997). “Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain.”. The Journal of Neuroscience. 17 (13): 5046–61. PMID9185542.
- Luskin, MB (Jul 1993). “Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone.”. Neuron. 11 (1): 173–89. PMID8338665. doi:1016/0896-6273(93)90281-U.
- Doetsch, F; Caillé, I; Lim, DA; García-Verdugo, JM; Alvarez-Buylla, A (Jun 11, 1999). “Subventricular zone astrocytes are neural stem cells in the adult mammalian brain.”. Cell. 97 (6): 703–16. PMID10380923. doi:1016/S0092-8674(00)80783-7.
- Lim, DA; Alvarez-Buylla, A (Jun 22, 1999). “Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis.”. Proceedings of the National Academy of Sciences of the United States of America. 96 (13): 7526–31. PMC22119 . PMID 10377448. doi:1073/pnas.96.13.7526.
- Gates, MA; Thomas, LB; Howard, EM; Laywell, ED; Sajin, B; Faissner, A; Götz, B; Silver, J; Steindler, DA (Oct 16, 1995). “Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres.”. The Journal of Comparative Neurology. 361 (2): 249–66. PMID8543661. doi:1002/cne.903610205.
- Aguirre A, Rubio ME, Gallo V (September 1998). “Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal”. Nat.. 467 (7313): 323–7. PMC2941915 . PMID 20844536. doi:1038/nature09347.
- Bernier, PJ; Vinet, J; Cossette, M; Parent, A (May 2000). “Characterization of the subventricular zone of the adult human brain: evidence for the involvement of Bcl-2.”. Neuroscience research. 37 (1): 67–78. PMID10802345. doi:1016/S0168-0102(00)00102-4.
- Parent JM, von dem Bussche N, Lowenstein DH (2006). “Prolonged seizures recruit caudal subventricular zone glial progenitors into the injured hippocampus.”. Hippocampus. 16 (3): 321–8. PMID16435310. doi:1002/hipo.20166.
- Piccirillo, Sara G. M.; Spiteri, Inmaculada; Sottoriva, Andrea; Touloumis, Anestis; Ber, Suzan; Price, Stephen J.; Heywood, Richard; Francis, Nicola-Jane; Howarth, Karen D. (2015-01-01). “Contributions to Drug Resistance in Glioblastoma Derived from Malignant Cells in the Sub-Ependymal Zone”. Cancer Research. 75 (1): 194–202. ISSN0008-5472. PMC 4286248 . PMID 25406193. doi:1158/0008-5472.CAN-13-3131.
- Mistry, A. et. al. (2016). “Influence of glioblastoma contact with the lateral ventricle on survival: a meta-analysis”. J Neurooncol. PMID27644688. doi:1007/s11060-016-2278-7.
- Mistry, A. et. al. (2017). “Decreased survival in glioblastomas is specific to contact with the ventricular-subventricular zone, not subgranular zone or corpus callosum”. J Neurooncol. PMID28074322. doi:1007/s11060-017-2374-3.