A Comparison of the Patterns of Migration and the Destinations of Homotopically Transplanted Neonatal Subventricular Zone Cells and Heterotopically Transplanted Telencephalic Ventricular Zone Cells

There is intense interest and effort toward regenerating the brain after severe injury. Stem cell transplantation after insult to the central nervous system has been regarded as the most promising approach for repair; however, engrafting cells alone might not be sufficient for effective regeneration. In this study, we have compared neural progenitors (NPs) from the fetal ventricular zone (VZ), the postnatal subventricular zone, and an immortalized radial glia (RG) cell line engineered to conditionally secrete the trophic factor insulin-like growth factor 1 (IGF-1). Upon differentiation in vitro, the VZ cells were able to generate a greater number of neurons than subventricular zone cells. Furthermore, differentiated VZ cells generated pyramidal neurons . In vitro, doxycycline-driven secretion of IGF-1 strongly promoted neuronal differentiation of cells with hippocampal, interneuron and cortical specificity. Accordingly, VZ and engineered RG-IGF-1-hemagglutinin (HA) cells were selected for subsequent in vivo experiments. To increase cell survival, we delivered the NPs attached to a multifunctional chitosan-based scaffold. The microspheres containing adherent NPs were injected subacutely into the lesion cavity of adult rat brains that had sustained controlled cortical impact injury. At 2 weeks posttransplantation, the exogenously introduced cells showed a reduction in stem cell or progenitor markers and acquired mature neuronal and glial markers. In beam walking tests assessing sensorimotor recovery, transplanted RG cells secreting IGF-1 contributed significantly to functional improvement while native VZ or RG cells did not promote significant recovery. Altogether, these results support the therapeutic potential of chitosan-based multifunctional microsphere scaffolds seeded with genetically modified NPs expressing IGF-1 to promote repair and functional recovery after traumatic brain injuries.

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The Subventricular Zone: A Key Player in Human Neocortical Development

The Neuroscientist ◽

10.1177/1073858417691009 ◽

2017 ◽

Vol 24 (2) ◽

pp. 156-170 ◽

Cited By ~ 10

Author(s):

J. Alberto Ortega ◽

Fani Memi ◽

Nevena Radonjic ◽

Radmila Filipovic ◽

Inseyah Bagasrawala ◽

...

Keyword(s):

Cerebral Cortex ◽

Subventricular Zone ◽

Ventricular Zone ◽

Cell Types ◽

Projection Neurons ◽

Cortical Projection ◽

Intrauterine Development ◽

Vitro Model ◽

Primate Cerebral Cortex

One of the main characteristics of the developing brain is that all neurons and the majority of macroglia originate first in the ventricular zone (VZ), next to the lumen of the cerebral ventricles, and later on in a secondary germinal area above the VZ, the subventricular zone (SVZ). The SVZ is a transient compartment mitotically active in humans for several gestational months. It serves as a major source of cortical projection neurons as well as an additional source of glial cells and potentially some interneuron subpopulations. The SVZ is subdivided into the smaller inner (iSVZ) and the expanded outer SVZ (oSVZ). The enlargement of the SVZ and, in particular, the emergence of the oSVZ are evolutionary adaptations that were critical to the expansion and unique cellular composition of the primate cerebral cortex. In this review, we discuss the cell types and organization of the human SVZ during the first half of the 40 weeks of gestation that comprise intrauterine development. We focus on this period as it is when the bulk of neurogenesis in the human cerebral cortex takes place. We consider how the survival and fate of SVZ cells depend on environmental influences, by analyzing the results from in vitro experiments with human cortical progenitor cells. This in vitro model is a powerful tool to better understand human neocortex formation and the etiology of neurodevelopmental disorders, which in turn will facilitate the design of targeted preventive and/or therapeutic strategies.

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Mimicking Neural Stem Cell Niche by Biocompatible Substrates

Stem Cells International ◽

10.1155/2016/1513285 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 14

Author(s):

Citlalli Regalado-Santiago ◽

Enrique Juárez-Aguilar ◽

Juan David Olivares-Hernández ◽

Elisa Tamariz

Keyword(s):

Subventricular Zone ◽

Current Knowledge ◽

Ventricular Zone ◽

Neurogenic Niche ◽

Extracellular Matrix Components ◽

The Central Nervous System ◽

Cell Niche ◽

Extracellular Environment

Neural stem cells (NSCs) participate in the maintenance, repair, and regeneration of the central nervous system. During development, the primary NSCs are distributed along the ventricular zone of the neural tube, while, in adults, NSCs are mainly restricted to the subependymal layer of the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. The circumscribed areas where the NSCs are located contain the secreted proteins and extracellular matrix components that conform their niche. The interplay among the niche elements and NSCs determines the balance between stemness and differentiation, quiescence, and proliferation. The understanding of niche characteristics and how they regulate NSCs activity is critical to buildingin vitromodels that include the relevant components of thein vivoniche and to developing neuroregenerative approaches that consider the extracellular environment of NSCs. This review aims to examine both the current knowledge on neurogenic niche and how it is being used to develop biocompatible substrates for thein vitroandin vivomimicking of extracellular NSCs conditions.

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Mash1 regulates neurogenesis in the ventral telencephalon

Development ◽

10.1242/dev.126.3.525 ◽

1999 ◽

Vol 126 (3) ◽

pp. 525-534 ◽

Cited By ~ 29

Author(s):

S. Casarosa ◽

C. Fode ◽

F. Guillemot

Keyword(s):

Nervous System ◽

Notch Signaling ◽

Subventricular Zone ◽

Ventricular Zone ◽

Ganglionic Eminence ◽

Ventral Telencephalon ◽

Neuronal Populations ◽

Neuronal Precursors ◽

Important Regulator ◽

The Central Nervous System

Previous studies have shown that mice mutant for the gene Mash1 display severe neuronal losses in the olfactory epithelium and ganglia of the autonomic nervous system, demonstrating a role for Mash1 in development of neuronal lineages in the peripheral nervous system. Here, we have begun to analyse Mash1 function in the central nervous system, focusing our studies on the ventral telencephalon where it is expressed at high levels during neurogenesis. Mash1 mutant mice present a severe loss of progenitors, particularly of neuronal precursors in the subventricular zone of the medial ganglionic eminence. Discrete neuronal populations of the basal ganglia and cerebral cortex are subsequently missing. An analysis of candidate effectors of Mash1 function revealed that the Notch ligands Dll1 and Dll3, and the target of Notch signaling Hes5, fail to be expressed in Mash1 mutant ventral telencephalon. In the lateral ganglionic eminence, loss of Notch signaling activity correlates with premature expression of a number of subventricular zone markers by ventricular zone cells. Therefore, Mash1 is an important regulator of neurogenesis in the ventral telencephalon, where it is required both to specify neuronal precursors and to control the timing of their production.

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Expression Profile of Sonic Hedgehog Pathway Members in the Developing Human Fetal Brain

BioMed Research International ◽

10.1155/2015/494269 ◽

2015 ◽

Vol 2015 ◽

pp. 1-15 ◽

Cited By ~ 5

Author(s):

Julia Tichy ◽

Jenny Zinke ◽

Benedikt Bunz ◽

Richard Meyermann ◽

Patrick N. Harter ◽

...

Keyword(s):

Sonic Hedgehog ◽

Subventricular Zone ◽

Granular Layer ◽

Ventricular Zone ◽

Fetal Brain ◽

Cortical Plate ◽

Temporal Expression ◽

Spatiotemporal Expression ◽

Pathway Expression ◽

Proliferation And Differentiation

The Sonic Hedgehog (SHH) pathway plays a central role in the developing mammalian CNS. In our study, we aimed to investigate the spatiotemporalSHHpathway expression pattern in human fetal brains. We analyzed 22 normal fetal brains for Shh, Patched, Smoothened, and Gli1-3 expression by immunohistochemistry. In the telencephalon, strongest expression of Shh, Smoothened, and Gli2 was found in the cortical plate (CP) and ventricular zone. Patched was strongly upregulated in the ventricular zone and Gli1 in the CP. In the cerebellum,SHHpathway members were strongly expressed in the external granular layer (EGL).SHHpathway members significantly decreased over time in the ventricular and subventricular zone and in the cerebellar EGL, while increasing levels were found in more superficial telencephalic layers. Our findings show thatSHHpathway members are strongly expressed in areas important for proliferation and differentiation and indicate a temporal expression gradient in telencephalic and cerebellar layers probably due to decreased proliferation of progenitor cells and increased differentiation. Our data about the spatiotemporal expression ofSHHpathway members in the developing human brain serves as a base for the understanding of both normal and pathological CNS development.

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MiR-137 and miR-122, two outer subventricular zone-enriched non-coding RNAs, regulate basal progenitor expansion and neuronal differentiation

10.1101/2021.04.01.438039 ◽

2021 ◽

Author(s):

Ugo Tomasello ◽

Esther Klingler ◽

Mathieu Niquille ◽

Nandkishor Mule ◽

Laura de Vevey ◽

...

Keyword(s):

Neuronal Differentiation ◽

Subventricular Zone ◽

Ventricular Zone ◽

Superficial Layer ◽

Basal Progenitor ◽

Germinal Zone ◽

Layer Neuron ◽

A Cell ◽

Non Coding Rnas

Cortical expansion in the primate brain relies on the presence and the spatial enlargement of multiple germinal zones during development and on a prolonged developmental period. In contrast to other mammals, which have two cortical germinal zones, the ventricular zone (VZ) and subventricular zone (SVZ), gyrencephalic species display an additional germinal zone, the outer subventricular zone (OSVZ), which role is to increase the number and types of neurons generated during corticogenesis. How the OSVZ emerged during evolution is poorly understood but recent studies suggest a role for non-coding RNAs, which allow tight regulations of transcriptional programs in time and space during development (Dehay et al. 2015; Arcila et al., 2014). Here, using in vivo functional genetics, single-cell RNA sequencing, live imaging and electrophysiology to assess progenitor and neuronal properties in mice, we identify two ferret and human OSVZ-enriched microRNAs (miR), miR-137 and miR-122, which regulate key cellular features associated with cortical expansion. MiR-137 promotes basal progenitor self-replication and superficial layer neuron fate, while miR-122 slows down neuronal differentiation pace. Together, these findings support a cell-type specific role for miR-mediated transcriptional regulation in cortical expansion.

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Differential Fatty Acid-Binding Protein Expression in Persistent Radial Glia in the Human and Sheep Subventricular Zone

Developmental Neuroscience ◽

10.1159/000487633 ◽

2018 ◽

Vol 40 (2) ◽

pp. 145-161 ◽

Cited By ~ 4

Author(s):

Birger Victor Dieriks ◽

Justin M. Dean ◽

Eleonora Aronica ◽

Henry J. Waldvogel ◽

Richard L.M. Faull ◽

...

Keyword(s):

Fatty Acid ◽

Subventricular Zone ◽

Intracellular Transport ◽

Radial Glia ◽

Ventricular Zone ◽

Nuclear Antigen ◽

Fatty Acid Binding Proteins ◽

Specific Expression ◽

Fatty Acid Binding ◽

Adult Human

Fatty acid-binding proteins (FABPs) are a family of transport proteins that facilitate intracellular transport of fatty acids. Despite abundant expression in the brain, the role that FABPs play in the process of cell proliferation and migration in the subventricular zone (SVZ) remains unclear. Our results provide a detailed characterisation of FABP3, 5, and 7 expression in adult and fetal human and sheep SVZ. High FABP5 expression was specifically observed in the adult human SVZ and co-labelled with polysialylated neural cell adhesion molecule (PSA-NCAM), glial fibrillary acidic protein (GFAP), GFAPδ, and proliferating cell nuclear antigen (PCNA), indicating a role for FABP5 throughout the full maturation process of astrocytes and neuroblasts. Some FABP5+ cells had a radial glial-like appearance and co-labelled with the radial glia markers vimentin (40E-C) and GFAP. In the fetal human brain, FABP5 was expressed by radial glia cells throughout the ventricular zone. In contrast, radial glia-like cells in sheep highly expressed FABP3. Taken together, these differences highlight the species-specific expression profile of FABPs in the SVZ. In this study, we demonstrate the distribution of FABP in the adult human SVZ and fetal ventricular zone and reveal its expression on persistent radial glia that may be involved in adult neurogenesis.

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Telencephalon enlargement by the convergent evolution of expanded subventricular zones

Biology Letters ◽

10.1098/rsbl.2008.0439 ◽

2008 ◽

Vol 5 (1) ◽

pp. 134-137 ◽

Cited By ~ 16

Author(s):

Georg F Striedter ◽

Christine J Charvet

Keyword(s):

Subventricular Zone ◽

Convergent Evolution ◽

Ventricular Zone ◽

Proliferating Cells ◽

Mantle Zone ◽

Subventricular Zones ◽

Mechanical Constraint ◽

Mitotic Cells

Some mammals and birds independently evolved an enlarged telencephalon. They appear to have done so, at least in part, by developing a thick telencephalic subventricular zone (SVZ). We suggest that this correlation between telencephalic enlargement and SVZ expansion is due to a mechanical constraint acting on the proliferative ventricular zone (VZ). Essentially, we argue that rapid proliferation in the VZ after post-mitotic cells in the overlying mantle zone have begun to form limits the VZ's tangential expandability and forces some proliferating cells to emigrate from the VZ and expand the pool of proliferating cells that comprise the SVZ.

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A role for Gsh1 in the developing striatum and olfactory bulb of Gsh2 mutant mice

Development ◽

10.1242/dev.128.23.4769 ◽

2001 ◽

Vol 128 (23) ◽

pp. 4769-4780 ◽

Cited By ~ 5

Author(s):

Håkan Toresson ◽

Kenneth Campbell

Keyword(s):

Olfactory Bulb ◽

Subventricular Zone ◽

Ventricular Zone ◽

Cell Number ◽

Mutant Mice ◽

Ganglionic Eminence ◽

Ventral Telencephalon ◽

Molecular Identity ◽

Lateral Ganglionic Eminence

We have examined the role of the two closely related homeobox genes Gsh1 and Gsh2, in the development of the striatum and the olfactory bulb. These two genes are expressed in a partially overlapping pattern by ventricular zone progenitors of the ventral telencephalon. Gsh2 is expressed in both of the ganglionic eminences while Gsh1 is largely confined to the medial ganglionic eminence. Previous studies have shown that Gsh2–/– embryos suffer from an early misspecification of precursors in the lateral ganglionic eminence (LGE) leading to disruptions in striatal and olfactory bulb development. This molecular misspecification is present only in early precursor cells while at later stages the molecular identity of these cells appears to be normalized. Concomitant with this normalization, Gsh1 expression is notably expanded in the Gsh2–/– LGE. While no obvious defects in striatal or olfactory bulb development were detected in Gsh1–/– embryos, Gsh1/2 double homozygous mutants displayed more severe disruptions than were observed in the Gsh2 mutant alone. Accordingly, the molecular identity of LGE precursors in the double mutant is considerably more perturbed than in Gsh2 single mutants. These findings, therefore, demonstrate an important role for Gsh1 in the development of the striatum and olfactory bulb of Gsh2 mutant mice. In addition, our data indicate a role for Gsh genes in controlling the size of the LGE precursor pools, since decreasing copies of Gsh2 and Gsh1 alleles results in a notable decrease in precursor cell number, particularly in the subventricular zone.

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Transcriptional heterogeneity of ventricular zone cells throughout the embryonic mouse forebrain

10.1101/2021.07.05.451224 ◽

2021 ◽

Author(s):

Dongjin R Lee ◽

Christopher Rhodes ◽

Apratim Mitra ◽

Yajun Zhang ◽

Dragan Maric ◽

...

Keyword(s):

Gene Expression ◽

Cell Fate ◽

Subventricular Zone ◽

Radial Glia ◽

Ventricular Zone ◽

Embryonic Mouse ◽

Transgenic Mouse Line ◽

Differential Gene ◽

Temporal Genetic Diversity

The ventricular zone (VZ) of the nervous system contains radial glia cells that were originally considered relatively homogenous in their gene expression. However, a detailed characterization of transcriptional diversity in these VZ cells has not been reported. Here, we performed single-cell RNA sequencing to characterize transcriptional heterogeneity of neural progenitors within the VZ and subventricular zone (SVZ) of the mouse embryonic cortex and ganglionic eminences (GEs). By using a transgenic mouse line to enrich for VZ cells, we detect significant transcriptional heterogeneity within VZ and SVZ progenitors, both between forebrain regions and within spatial subdomains of specific GEs. Additionally, we observe differential gene expression between E12.5 and E14.5 VZ cells, which could provide insights into temporal changes in cell fate. Together, our results reveal a previously unknown spatial and temporal genetic diversity of telencephalic VZ cells that will aid our understanding of initial fate decisions in the forebrain.

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