Ventricle Subventricular Zone Research Articles

Expression of D5 dopamine receptors in the lateral ventricle walls during post-weaning rat development.

Even before the first synapses appear, neurotransmitters and their receptors are present in the developing brain, regulating the cell fate of neuronal progenitors in neurogenic niches, such as the lateral ventricle. In particular, dopamine appears to play a pivotal role in the neurogenesis of the subventricular zone by controlling the proliferation and differentiation of progenitors through activation of different receptors. Although dopamine receptor 5 (D5R) is expressed prenatally, there is little information regarding its role in either pre- or postnatal forebrain development. To examine the role of D5Rs in neurogenesis in the rat lateral ventricle subventricular zone (V-SVZ), we immunohistochemically defined D5R expression, as well as BrdU incorporation in progenitor cells of various post-weaning stages (Post-natal day (P) 20 until P80). We found that the level of proliferating cells is stable from postnatal day 20 until 50, and then declines sharply on P80. Concomitantly, D5R is expressed in all ages examined, but we detected a progressive decrease in the density of D5R+ cells from P40 until P80. Moreover, double immunostaining for BrdU and D5R revealed that proliferating cells in V-SVZ also express D5R. Collectively, our data suggest that D5R is expressed in the post-weaning V-SVZ of rat at least until P80, and its expression pattern coincides with that of proliferating cells in the V-SVZ, hinting at a possible role of D5Rs in the regulation of neuronal progenitor division/differentiation.

Neural Precursor Cell-Derived Pleiotrophin Mediates Glioma Invasion of the Subventricular Zone

The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecular mechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knockdown starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion.

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma

The lateral ventricle subventricular zone (SVZ) is a frequent and consequential site of pediatric and adult glioma spread, but the cellular and molecularmechanisms mediating this are poorly understood. We demonstrate that neural precursor cell (NPC):glioma cell communication underpins this propensity of glioma to colonize the SVZ through secretion of chemoattractant signals toward which glioma cells home. Biochemical, proteomic, and functional analyses of SVZ NPC-secreted factors revealed the neurite outgrowth-promoting factor pleiotrophin, along with required binding partners SPARC/SPARCL1 and HSP90B, as key mediators of this chemoattractant effect. Pleiotrophin expression is strongly enriched in the SVZ, and pleiotrophin knock down starkly reduced glioma invasion of the SVZ in the murine brain. Pleiotrophin, in complex with the binding partners, activated glioma Rho/ROCK signaling, and ROCK inhibition decreased invasion toward SVZ NPC-secreted factors. These findings demonstrate a pathogenic role for NPC:glioma interactions and potential therapeutic targets to limit glioma invasion. PAPERCLIP.

Prdm16 is required for the maintenance of neural stem cells in the postnatal forebrain and their differentiation into ependymal cells.

We and others showed previously that PR domain-containing 16 (Prdm16) is a transcriptional regulator required for stem cell function in multiple fetal and neonatal tissues, including the nervous system. However, Prdm16 germline knockout mice died neonatally, preventing us from testing whether Prdm16 is also required for adult stem cell function. Here we demonstrate that Prdm16 is required for neural stem cell maintenance and neurogenesis in the adult lateral ventricle subventricular zone and dentate gyrus. We also discovered that Prdm16 is required for the formation of ciliated ependymal cells in the lateral ventricle. Conditional Prdm16 deletion during fetal development using Nestin-Cre prevented the formation of ependymal cells, disrupting cerebrospinal fluid flow and causing hydrocephalus. Postnatal Prdm16 deletion using Nestin-CreERT2 did not cause hydrocephalus or prevent the formation of ciliated ependymal cells but caused defects in their differentiation. Prdm16 was required in neural stem/progenitor cells for the expression of Foxj1, a transcription factor that promotes ependymal cell differentiation. These studies show that Prdm16 is required for adult neural stem cell maintenance and neurogenesis as well as the formation of ependymal cells.

In Vivo Administration of Cerebrospinal Fluid of Patients with Multiple Sclerosis; A New Model to Study Adult Neurogenesis in Different Stages of Disease

Multiple sclerosis (MS) is an autoimmune and demyelinating disease, affecting the central nervous system causing a wide spectrum of signs and symptoms. In adult mammalian brain, neural progenitor cells (NPCs) are placed in the subventricular zone of ventricles, subgranular zone of the dentate gyrus and give rise to new cells. In addition, alterations in adult neurogenesis are implicated in psychiatric disease in humans. Currently, there is no satisfactory evidence to describe how neurogenesis changes during pathogenesis of MS disease. It can be because of the lack of suitable animal model that represents pathogenesis of different stages of MS disease. Given that, cerebrospinal fluid (CSF) as a mirror can reflects major part of pathological conditions of disease in vivo administration of CSF derived from patients in to the brain ventricles of mice can lead to an experimental animal model for studying neurogenesis and other pathophysiology of multiple sclerosis. This strategy will help researchers to unravel the mechanisms in which neurogenesis changes in different stages of MS disease.

Prospective identification of functionally distinct stem cells and neurosphere-initiating cells in adult mouse forebrain.

Neurosphere formation is commonly used as a surrogate for neural stem cell (NSC) function but the relationship between neurosphere-initiating cells (NICs) and NSCs remains unclear. We prospectively identified, and isolated by flow cytometry, adult mouse lateral ventricle subventricular zone (SVZ) NICs as Glast(mid)EGFR(high)PlexinB2(high)CD24(-/low)O4/PSA-NCAM(-/low)Ter119/CD45(-) (GEPCOT) cells. They were highly mitotic and short-lived in vivo based on fate-mapping with Ascl1(CreERT2) and Dlx1(CreERT2). In contrast, pre-GEPCOT cells were quiescent, expressed higher Glast, and lower EGFR and PlexinB2. Pre-GEPCOT cells could not form neurospheres but expressed the stem cell markers Slc1a3-CreER(T), GFAP-CreER(T2), Sox2(CreERT2), and Gli1(CreERT2) and were long-lived in vivo. While GEPCOT NICs were ablated by temozolomide, pre-GEPCOT cells survived and repopulated the SVZ. Conditional deletion of the Bmi-1 polycomb protein depleted pre-GEPCOT and GEPCOT cells, though pre-GEPCOT cells were more dependent upon Bmi-1 for Cdkn2a (p16(Ink4a)) repression. Our data distinguish quiescent NSCs from NICs and make it possible to study their properties in vivo.DOI: http://dx.doi.org/10.7554/eLife.02669.001.

Biciliated ependymal cell proliferation contributes to spinal cord growth

Two neurogenic regions have been described in the adult brain, the lateral ventricle subventricular zone and the dentate gyrus subgranular zone. It has been suggested that neural stem cells also line the central canal of the adult spinal cord. Using transmission and scanning electron microscopy and immunostaining, we describe here the organization and cell types of the central canal epithelium in adult mice. The identity of dividing cells was determined by 3D ultrastructural reconstructions of [(3) H]thymidine-labeled cells and confocal analysis of bromodeoxyuridine labeling. The most common cell type lining the central canal had two long motile (9+2) cilia and was vimentin+, CD24+, FoxJ1+, Sox2+, and CD133+, but nestin- and glial fibrillary acidic protein (GFAP)-. These biciliated ependymal cells of the central canal (Ecc) resembled E2 cells of the lateral ventricles, but their basal bodies were different from those of E2 or E1 cells. Interestingly, we frequently found Ecc cells with two nuclei and four cilia, suggesting they are formed by incomplete cytokinesis or cell fusion. GFAP+ astrocytes with a single cilium and an orthogonally oriented centriole were also observed. The majority of dividing cells corresponded to biciliated Ecc cells. Central canal proliferation was most common during the active period of spinal cord growth. Pairs of labeled Ecc cells were observed within the central canal in adult mice 2.5 weeks post labeling. Our work suggests that the vast majority of postnatal dividing cells in the central canal are Ecc cells and their proliferation is associated with the growth of the spinal cord.

Innate Neural Stem Cell Heterogeneity Determines the Patterning of Glioma Formation in Children

The concept that gliomas comprise a heterogeneous group of diseases distinguished by their developmental origin raises the intriguing possibility that neural stem cells (NSCs) from different germinal zones have differential capacities to respond to glioma-causing genetic changes. We demonstrate that lateral ventricle subventricular zone NSCs are molecularly and functionally distinct from those of the third ventricle. Consistent with a unique origin for pediatric low-grade glioma, third ventricle, but not lateral ventricle, NSCs hyperproliferate in response to mutations characteristic of childhood glioma. Finally, we demonstrate that pediatric optic gliomas in Nf1 genetically engineered mice arise from the third ventricle. Collectively, these observations establish the importance of innate brain region NSC heterogeneity in the patterning of gliomagenesis in children and adults.

Comparative Characterization of the Human and Mouse Third Ventricle Germinal Zones

Recent evidence indicates differences in neural stem cell biology in different brain regions. For example, we demonstrated that neurofibromatosis 1 (NF1) tumor suppressor gene inactivation leads to increased neural stem cell proliferation and gliogenesis in the optic chiasm and brainstem but not in the cerebral cortex. The differential effect of Nf1 inactivation in the optic nerve and brainstem (in which gliomas commonly form in children with NF1) versus the cortex (in which gliomas rarely develop) suggests the existence of distinct ventricular zones for gliomagenesis in children and in adults. Here, we characterized the third ventricle subventricular zone (tv-SVZ) in young and adult mouse and human brains. In children, but not adult humans, the tv-SVZ contains nestin-positive, glial fibrillary acidic protein-positive, brain fatty acid binding protein-positive, and sox2-positive cells with radial processes and prominent cilia. In contrast, the tv-SVZ in young mice contains sox2-positive progenitor cells and ciliated ependymal lining cells but lacks glial fibrillary acidic protein-positive, nestin-positive radial glia. As in the lateral ventricle SVZ, proliferation in the human and murine tv-SVZ decreases with age. The tv-SVZ in adult mice lacks the hypocellular subventricular zone observed in adult human specimens. Collectively, these data indicate the existence of a subventricular zone relevant to our understanding of glioma formation in children and will assist interpretation of genetically engineered mouse glioma models.