scholarly journals Apical progenitors remain multipotent throughout cortical neurogenesis

2018 ◽  
Author(s):  
Polina Oberst ◽  
Sabine Fièvre ◽  
Natalia Baumann ◽  
Cristina Concetti ◽  
Denis Jabaudon
Keyword(s):  
Ventricular Zone ◽  
Superficial Layer ◽  
High Temporal Resolution ◽  
Fate Map ◽  
Pulse Label ◽  
Intermediate Progenitors ◽  
Multipotent Cells ◽  
Cell Type Specific ◽  
Temporal Identity ◽  
Fate Restriction

The diverse subtypes of excitatory neurons that populate the neocortex are born from progenitors located in the ventricular zone (apical progenitors, APs). During corticogenesis, APs progress through successive temporal states to sequentially generate deep- followed by superficial-layer neurons directly or via the generation of intermediate progenitors (IPs). Yet little is known about the plasticity of AP temporal identity and whether individual progenitor subtypes remain multipotent throughout corticogenesis. To address this question, we used FlashTag (FT), a method to pulse-label and isolate APs in the mouse neocortex with high temporal resolution to fate-map neuronal progeny following heterochronic transplantation of APs into younger embryos. We find that unlike daughter IPs, which lose the ability to generate deep layer neurons when transplanted into a younger host, APs are temporally uncommitted and become molecularly respecified to generate normally earlier-born neuron types. These results indicate that APs are multipotent cells that are able to revert their temporal identity and re-enter past molecular and neurogenic states. AP fate progression thus occurs without detectable fate restriction during the neurogenic period of corticogenesis. These findings identify unforeseen cell-type specific differences in cortical progenitor fate plasticity, which could be exploited for neuroregenerative purposes.

scholarly journals Simultaneous production of diverse neuronal subtypes during early corticogenesis

2018 ◽  
Author(s):  
E. Magrinelli ◽  
R. J. Wagener ◽  
D. Jabaudon
Keyword(s):  
Deep Layer ◽  
Ventricular Zone ◽  
Neuronal Cell ◽  
Cell Types ◽  
Superficial Layer ◽  
High Temporal Resolution ◽  
Fine Grained ◽  
Molecular Identity ◽  
Deep Layers ◽  
Successive Generations

AbstractThe circuits of the neocortex are composed of a broad diversity of neuronal cell types, which can be distinguished by their laminar location, molecular identity, and connectivity. During embryogenesis, successive generations of glutamatergic neurons are sequentially born from progenitors located in germinal zones below the cortex. In this process, the earliest-born generations of neurons differentiate to reside in deep layers, while later-born daughter neurons reside in more superficial layers. Although the aggregate competence of progenitors to produce successive subtypes of neurons progresses as corticogenesis proceeds, a fine-grained temporal understanding of how neuronal subtypes are sequentially produced is still missing. Here, we use FlashTag, a high temporal resolution labeling approach, to follow the fate of the simultaneously-born daughter neurons of ventricular zone progenitors at multiple stages of corticogenesis. Our findings reveal a bimodal regulation in the diversity of neurons being produced at single time points of corticogenesis. Initially, distinct subtypes of deep-layer neurons are simultaneously produced, as defined by their laminar location, molecular identity and connectivity. Later on, instead, instantaneous neuronal production is homogeneous and the distinct superficial-layer neurons subtypes are sequentially produced. These findings suggest that early-born, deep-layer neurons have a less determined fate potential than later-born superficial layer neurons, which may reflect the progressive implementation of pre-and/or post-mitotic mechanisms controlling neuronal fate reliability.

scholarly journals Dab2IP Regulates Neuronal Positioning, Rap1 Activity and Integrin Signaling in the Developing Cortex

2015 ◽  
Vol 37 (2) ◽  
pp. 131-141 ◽  
Author(s):  
Shuhong Qiao ◽  
Ramin Homayouni
Keyword(s):  
Brain Development ◽  
Cortical Neurons ◽  
Ventricular Zone ◽  
Physiological Role ◽  
Immunohistochemical Analysis ◽  
Superficial Layer ◽  
Tumor Formation ◽  
Intermediate Zone ◽  
Cortical Plate ◽  
Integrin Signaling

Dab2IP (DOC-2/DAB2 interacting protein) is a GTPase-activating protein which is involved in various aspects of brain development in addition to its roles in tumor formation and apoptosis in other systems. In this study, we carefully examined the expression profile of Dab2IP and investigated its physiological role during brain development using a Dab2IP-knockdown (KD) mouse model created by retroviral insertion of a LacZ-encoding gene-trapping cassette. LacZ staining revealed that Dab2IP is expressed in the ventricular zone as well as the cortical plate and the intermediate zone. Immunohistochemical analysis showed that Dab2IP protein is localized in the leading process and proximal cytoplasmic regions of migrating neurons in the intermediate zone. Bromodeoxyuridine birth dating experiments in combination with immunohistochemical analysis using layer-specific markers showed that Dab2IP is important for proper positioning of a subset of layer II-IV neurons in the developing cortex. Notably, neuronal migration was not completely disrupted in the cerebral cortex of Dab2IP-KD mice and disruption of migration was not strictly layer specific. Previously, we found that Dab2IP regulates multipolar transition in cortical neurons. Others have shown that Rap1 regulates the transition from multipolar to bipolar morphology in migrating postmitotic neurons through N-cadherin signaling and somal translocation in the superficial layer of the cortical plate through integrin signaling. Therefore, we examined whether Rap1 and integrin signaling were affected in Dab2IP-KD brains. We found that Dab2IP-KD resulted in higher levels of activated Rap1 and integrin in the developing cortex. Taken together, our results suggest that Dab2IP plays an important role in the migration and positioning of a subpopulation of later-born (layers II-IV) neurons, likely through the regulation of Rap1 and integrin signaling.

scholarly journals Preterm Intraventricular Hemorrhage in vitro: Modeling the Cytopathology of the Ventricular Zone

2020 ◽  
Author(s):  
Leandro Castaneyra-Ruiz ◽  
James P. McAllister ◽  
Diego M. Morales ◽  
Steven L. Brody ◽  
Albert M. Isaacs ◽  
...  
Keyword(s):  
Intraventricular Hemorrhage ◽  
In Vitro Model ◽  
Ependymal Cell ◽  
Ventricular Zone ◽  
High Temporal Resolution ◽  
Neuroepithelial Cells ◽  
Vitro Model ◽  
Developmental Features ◽  
The Impact

Abstract Background: Severe intraventricular hemorrhage (IVH) is one of the most devastating neurological complications in preterm infants, with the majority suffering long-term neurological morbidity and up to 50 percent developing post hemorrhagic hydrocephalus (PHH). Despite the importance of this disease, its cytopathological mechanisms are not well known. An in vitro model of IVH is required to investigate the effects of blood and its components on the developing ventricular zone (VZ) and its stem cell niche. To address this need, we developed a new in vitro model to mimic the cytopathological conditions of IVH in the preterm infant. Methods: Maturing neuroepithelial cells from the VZ were harvested from the entire lateral ventricles of wild type C57BL/6 mice at 1-4 days of age and expanded in proliferation media for 3-5 days. At confluence, cells were re-plated onto 24-well plates in differentiation media to generate ependymal cells (EC). At approximately 3-5 days, which corresponded to the onset of ependymal cell differentiation based on the appearance of multiciliated cells , phosphate-buffered saline for controls or syngeneic whole blood for IVH was added to the ependymal cell surface. The cells were examined for the expression of EC markers of differentiation and maturation to qualitatively and quantitatively assess the effect of blood exposure on VZ transition from neuroepithelial cells to EC. Discussion: This model will allow investigators to test cytopathological mechanisms contributing to the pathology of IVH with high temporal resolution and query the impact of injury to the maturation of the VZ. This technique recapitulates features of normal maturation of the VZ in vitro, offering the capacity to investigate the developmental features of VZ biogenesis.

scholarly journals Compartment and cell-type specific hypoxia responses in the developing Drosophila brain

Biology Open ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. bio053629
Author(s):  
Martin Baccino-Calace ◽  
Daniel Prieto ◽  
Rafael Cantera ◽  
Boris Egger
Keyword(s):  
Neural Cells ◽  
Cell Type ◽  
Larval Brain ◽  
Hypoxia Response ◽  
Stem Cell Maintenance ◽  
Intermediate Progenitors ◽  
Drosophila Brain ◽  
A Cell ◽  
Cell Type Specific ◽  
Hypoxic State

ABSTRACTEnvironmental factors such as the availability of oxygen are instructive cues that regulate stem cell maintenance and differentiation. We used a genetically encoded biosensor to monitor the hypoxic state of neural cells in the larval brain of Drosophila. The biosensor reveals brain compartment and cell-type specific levels of hypoxia. The values correlate with differential tracheolation that is observed throughout development between the central brain and the optic lobe. Neural stem cells in both compartments show the strongest hypoxia response while intermediate progenitors, neurons and glial cells reveal weaker responses. We demonstrate that the distance between a cell and the next closest tracheole is a good predictor of the hypoxic state of that cell. Our study indicates that oxygen availability appears to be the major factor controlling the hypoxia response in the developing Drosophila brain and that cell intrinsic and cell-type specific factors contribute to modulate the response in an unexpected manner.This article has an associated First Person interview with the first author of the paper.

scholarly journals Lis1 mutation prevents basal radial glia-like cell production in the mouse

2020 ◽  
Author(s):  
Maxime Penisson ◽  
Shinji Hirotsune ◽  
Fiona Francis ◽  
Richard Belvindrah
Keyword(s):  
Mitotic Spindle ◽  
Neuronal Migration ◽  
Radial Glia ◽  
Ventricular Zone ◽  
Specific Gene ◽  
Wild Type ◽  
Intermediate Progenitors ◽  
Gene Coding ◽  
Outer Radial Glia

AbstractHuman cortical malformations are associated with progenitor proliferation and neuronal migration abnormalities. Progenitor cells include apical radial glia, intermediate progenitors and basal (or outer) radial glia (bRGs or oRGs). bRGs are few in number in lissencephalic species (e.g. the mouse) but abundant in gyrencephalic brains. The LIS1 gene coding for a dynein regulator, is mutated in human lissencephaly, associated also in some cases with microcephaly. LIS1 was shown to be important during cell division and neuronal migration. Here, we generated bRG-like cells in the mouse embryonic brain, investigating the role of Lis1 in their formation. This was achieved by in utero electroporation of a hominoid-specific gene TBC1D3 (coding for a RAB-GAP protein) at mouse embryonic day (E) 14.5. We first confirmed that TBC1D3 expression in wild-type (WT) brain generates numerous Pax6+ bRG-like cells that are basally localized. Second, using the same approach, we assessed the formation of these cells in heterozygote Lis1 mutant brains. Our novel results show that Lis1 depletion in the forebrain from E9.5 prevented subsequent TBC1D3-induced bRG-like cell amplification. Indeed, we observe disruption of the ventricular zone (VZ) in the mutant. Lis1 depletion altered adhesion proteins and mitotic spindle orientations at the ventricular surface and increased the proportion of abventricular mitoses. Progenitor outcome could not be further altered by TBC1D3. We conclude that perturbation of Lis1/LIS1 dosage is likely to be detrimental for appropriate progenitor number and position, contributing to lissencephaly pathogenesis.

scholarly journals A Comprehensive Tool Set for Inducible, Cell Type-Specific Gene Expression in Arabidopsis

2018 ◽  
Author(s):  
Ann-Kathrin Schürholz ◽  
Vadir Lopez-Salmeron ◽  
Zhenni Li ◽  
Joachim Forner ◽  
Christian Wenzl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rapid Assessment ◽  
Cell Types ◽  
Specific Gene ◽  
High Temporal Resolution ◽  
Cell Type ◽  
Compensatory Mechanisms ◽  
Modern Biology ◽  
Control Of Gene Expression ◽  
Cell Type Specific

AbstractUnderstanding the context-specific role of gene function is a key objective of modern biology. To this end, we generated a resource for inducible cell-type specific trans-activation based on the well-established combination of the chimeric GR-LhG4 transcription factor and the synthetic pOp promoter. Harnessing the flexibility of the GreenGate cloning system, we produced a comprehensive set of GR-LhG4 driver lines targeting most tissues in the Arabidopsis shoot and root with a strong focus on the indeterminate meristems. We show that, when combined with effectors under control of the pOp promoter, tight temporal and spatial control of gene expression is achieved. In particular, inducible expression in F1 plants obtained from crosses of driver and effector lines allows rapid assessment of the cell type-specific impact of an effector with high temporal resolution. Thus, our comprehensive and flexible toolbox is suited to overcome the limitations of ubiquitous genetic approaches, the outputs of which are often difficult to interpret due to widespread existence of compensatory mechanisms and the integration of diverging effects in different cell types.One sentence summary: A set of lines enabling spatio-temporal control of gene expression in Arabidopsis.

scholarly journals Compartment and cell type-specific hypoxia responses in the developing Drosophila brain

2019 ◽  
Author(s):  
Martin Baccino-Calace ◽  
Daniel Prieto ◽  
Rafael Cantera ◽  
Boris Egger
Keyword(s):  
Neural Cells ◽  
Cell Type ◽  
Larval Brain ◽  
Hypoxia Response ◽  
Stem Cell Maintenance ◽  
Intermediate Progenitors ◽  
Drosophila Brain ◽  
A Cell ◽  
Cell Type Specific ◽  
Hypoxic State

ABSTRACTEnvironmental factors such as the availability of oxygen are instructive cues to regulate stem cell maintenance and differentiation. We used a genetically encoded biosensor to monitor the hypoxic state of neural cells in the larval brain of Drosophila. The biosensor reveals brain compartment and cell type specific levels of hypoxia. The values correlate with differential tracheolation that is observed throughout development between the central brain and the optic lobe. Neural stem cells in both compartments show the strongest hypoxia response while intermediate progenitors, neurons and glial cells reveal weaker responses. We demonstrate that the distance between a cell and the next closest tracheole is a good predictor of the hypoxic state for that cell. Our model concludes that oxygen availability is the major factor controlling the hypoxia response in the developing Drosophila brain but cell intrinsic and cell-type specific factors contribute to modulate the response in an unexpected manner.

scholarly journals Preterm intraventricular hemorrhage in vitro: modeling the cytopathology of the ventricular zone

2020 ◽  
Author(s):  
Leandro Castaneyra-Ruiz ◽  
James P. McAllister ◽  
Diego M. Morales ◽  
Steven L. Brody ◽  
Albert M. Isaacs ◽  
...  
Keyword(s):  
Intraventricular Hemorrhage ◽  
In Vitro Model ◽  
Ventricular Zone ◽  
Ependymal Cells ◽  
High Temporal Resolution ◽  
Neuroepithelial Cells ◽  
Vitro Model ◽  
Developmental Features ◽  
The Impact

Abstract Background: Severe intraventricular hemorrhage (IVH) is one of the most devastating neurological complications in preterm infants, with the majority suffering long-term neurological morbidity and up to 50 percent developing post-hemorrhagic hydrocephalus (PHH). Despite the importance of this disease, its cytopathological mechanisms are not well known. An in vitro model of IVH is required to investigate the effects of blood and its components on the developing ventricular zone (VZ) and its stem cell niche. To address this need, we developed a protocol from our accepted in vitro model to mimic the cytopathological conditions of IVH in the preterm infant. Methods: Maturing neuroepithelial cells from the VZ were harvested from the entire lateral ventricles of wild type C57BL/6 mice at 1-4 days of age and expanded in proliferation media for 3-5 days. At confluence, cells were re-plated onto 24-well plates in differentiation media to generate ependymal cells (EC). At approximately 3-5 days, which corresponded to the onset of EC differentiation based on the appearance of multiciliated cells, phosphate-buffered saline for controls or syngeneic whole blood for IVH was added to the EC surface. The cells were examined for the expression of EC markers of differentiation and maturation to qualitatively and quantitatively assess the effect of blood exposure on VZ transition from neuroepithelial cells to EC. Discussion: This protocol will allow investigators to test cytopathological mechanisms contributing to the pathology of IVH with high temporal resolution and query the impact of injury to the maturation of the VZ. This technique recapitulates features of normal maturation of the VZ in vitro, offering the capacity to investigate the developmental features of VZ biogenesis.

scholarly journals Distinct neural progenitor pools in the ventral telencephalon generate diversity in striatal spiny projection neurons

2019 ◽  
Author(s):  
Fran van Heusden ◽  
Anežka Macey-Dare ◽  
Rohan N. Krajeski ◽  
Andrew Sharott ◽  
Tommas Jan Ellender
Keyword(s):  
Neural Progenitor ◽  
Neural Progenitors ◽  
Projection Neurons ◽  
Spine Density ◽  
Striatal Neurons ◽  
Indirect Pathway ◽  
Pulse Label ◽  
Cortical Input ◽  
Intermediate Progenitors ◽  
Lateral Ganglionic Eminence

AbstractHeterogeneous populations of neural progenitors in the embryonic lateral ganglionic eminence (LGE) generate all GABAergic spiny projection neurons (SPNs) found in the striatum. Here we investigate how this diversity in neural progenitors relates to diversity of adult striatal neurons and circuits. Using a combination of in utero electroporation to fluorescently pulse-label striatal neural progenitors in the LGE, brain slice electrophysiology, electrical and optogenetic circuit mapping and immunohistochemistry, we characterise a population of neural progenitors enriched for apical intermediate progenitors (aIPs) and a distinct population of other progenitors (OPs) and their neural offspring. We find that neural progenitor origin has subtle but significant effects on the properties of striatal SPNs. Although aIP and OP progenitors can both generate D1-expressing direct pathway as well as D2-expressing indirect pathway SPNs found intermingled in the striatum, the aIP derived SPNs are found in more medial aspects of the striatum, exhibit more complex dendritic arbors with higher spine density and differentially sample cortical input. Moreover, optogenetic circuit mapping of the aIP derived neurons show that they further integrate within striatal circuits and innervate both local D1 and D2 SPNs. These results show that it is possible to fluorescently pulse-label distinct neural progenitor pools within the LGE and provide the first evidence that neural progenitor heterogeneity can contribute to the diversity of striatal SPNs.

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

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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