scholarly journals SNAP23 deficiency causes severe brain dysplasia through the loss of radial glial cell polarity

2020 ◽  
Vol 220 (1) ◽  
Author(s):  
Masataka Kunii ◽  
Yuria Noguchi ◽  
Shin-ichiro Yoshimura ◽  
Satoshi Kanda ◽  
Tomohiko Iwano ◽  
...  
Keyword(s):  
Neural Progenitor Cells ◽  
Cell Polarization ◽  
Snare Complex ◽  
Apical Plasma Membrane ◽  
Apical Surface ◽  
Radial Glial Cell ◽  
Radial Glial Cells ◽  
Junctional Complexes ◽  
Radial Glial ◽  
Intercellular Adhesions

In the developing brain, the polarity of neural progenitor cells, termed radial glial cells (RGCs), is important for neurogenesis. Intercellular adhesions, termed apical junctional complexes (AJCs), at the apical surface between RGCs are necessary for cell polarization. However, the mechanism by which AJCs are established remains unclear. Here, we show that a SNARE complex composed of SNAP23, VAMP8, and Syntaxin1B has crucial roles in AJC formation and RGC polarization. Central nervous system (CNS)–specific ablation of SNAP23 (NcKO) results in mice with severe hypoplasia of the neocortex and no hippocampus or cerebellum. In the developing NcKO brain, RGCs lose their polarity following the disruption of AJCs and exhibit reduced proliferation, increased differentiation, and increased apoptosis. SNAP23 and its partner SNAREs, VAMP8 and Syntaxin1B, are important for the localization of an AJC protein, N-cadherin, to the apical plasma membrane of RGCs. Altogether, SNARE-mediated localization of N-cadherin is essential for AJC formation and RGC polarization during brain development.

Stromal derived factor-1α in hippocampus radial glial cells in vitro regulates the migration of neural progenitor cells

2015 ◽  
Vol 39 (6) ◽  
pp. 750-758 ◽  
Author(s):  
Hui Ding ◽  
Guo-Hua Jin ◽  
Lin-Qing Zou ◽  
Xiao-Qing Zhang ◽  
Hao-Ming Li ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Glial Cells ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Radial Glial Cells ◽  
Radial Glial

scholarly journals Cell-Scale Modeling to Probe Mechanobiology during Early Cortical Development

2020 ◽  
Vol 3 ◽  
Author(s):  
Adam Lonnberg ◽  
Kara Garcia
Keyword(s):  
Glial Cells ◽  
Apical Surface ◽  
Cortical Folding ◽  
Radial Glial Cells ◽  
Scale Modeling ◽  
Modeling Software ◽  
Radial Glial ◽  
Radial Tension ◽  
Stochastic Production ◽  
Potential Impact

Background/Objective: During early cerebral cortex development, neurons form from proliferative glial cells near the ventricular (apical) surface, then migrate along radial glial scaffolds to the cortical surface. In species with wrinkled brains, the presence of basal radial glial cells (bRGCs), radial glial cells which have detached from the ventricular surface, is correlated to the process of gyrification. While mechanical forces are also involved in gyrus creation, the link between the mechanical and biological aspects of this process remains unelucidated. In this study, we hypothesized that radial tension may lead to the production of gyri via the intermediary creation of bRGCs.  Methods: To test this hypothesis, the cell-level modeling software CX3D was used to simulate a system in which radial tension acts on radial glial cells (RGCs), facilitating the semi-stochastic production of bRGCs during the process of neocortex development. The outcome of this model was contrasted with a control case in which bRGCs were not allowed to form, and the two models were compared based upon the presence of neurons on the basal surface.  Results: The production of bRGCs via tension corresponded to a significant increase in the presence of neurons on the pial surface, even if the total number of glial cells—and thus total number of neurons generated—remained constant. Additionally, the likelihood of neurons moving more basally was found to be significantly greater in the presence of bRGCs.  Conclusion and Potential Impact: These results were interpreted to be indications of early gyrus formation. Thus, this study showed that bRGCs—and, ultimately, gyri—may arise from mechanical tension, indicating a possible link between the biological and mechanical explanations of gyrus formation. By providing an alternative lens through which to understand cortical folding, this may have implications for future lines of inquiry, which may expand our understanding of neuro-pathologies associated with misfolding, such as autism and epilepsy. 

scholarly journals The ciliary gene INPP5E confers dorsal telencephalic identity to human cortical organoids by negatively regulating Sonic Hedgehog signalling

2021 ◽  
Author(s):  
Leah Schembs ◽  
Ariane Willems ◽  
Kerstin Hasenpusch-Theil ◽  
James D Cooper ◽  
Katie Whiting ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Primary Cilia ◽  
Cell Types ◽  
Negative Regulator ◽  
Apical Surface ◽  
Radial Glial Cells ◽  
Intracellular Signalling Pathways ◽  
Radial Glial ◽  
Sonic Hedgehog Signalling

Defects in primary cilia, cellular antennas that controls multiple intracellular signalling pathways, underlie several neurodevelopmental disorders, but how cilia control essential steps in human brain formation remains elusive. Here, we show that cilia are present on the apical surface of radial glial cells in human foetal forebrain. Interfering with cilia signalling in human organoids by mutating the INPP5E gene leads to the formation of ventral telencephalic cell types instead of cortical progenitors and neurons. INPP5E mutant organoids also showed increased SHH signalling and cyclopamine treatment partially rescued this ventralisation. In addition, ciliary expression of SMO was increased and the integrity of the transition zone was compromised. Overall, these findings establish the importance of primary cilia for dorsal/ventral patterning in human corticogenesis, indicate a tissue specific role of INPP5E as a negative regulator of SHH signalling and have implications for the emerging roles of cilia in the pathogenesis of neurodevelopmental disorders.

scholarly journals C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment

Development ◽  
2008 ◽  
Vol 135 (12) ◽  
pp. 2139-2149 ◽  
Author(s):  
A. K. Voss ◽  
J. M. Britto ◽  
M. P. Dixon ◽  
B. N. Sheikh ◽  
C. Collin ◽  
...  
Keyword(s):  
Cortical Neuron ◽  
Glial Cell ◽  
Cell Attachment ◽  
Radial Glial Cell ◽  
Neuron Migration ◽  
Radial Glial

Intracellular traffic of the ecto-nucleotide pyrophosphatase/phosphodiesterase NPP3 to the apical plasma membrane of MDCK and Caco-2 cells: apical targeting occurs in the absence of N-glycosylation

2000 ◽  
Vol 113 (23) ◽  
pp. 4193-4202 ◽  
Author(s):  
N.R. Meerson ◽  
V. Bello ◽  
J.L. Delaunay ◽  
T.A. Slimane ◽  
D. Delautier ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mdck Cells ◽  
Transmembrane Proteins ◽  
Cell Types ◽  
Apical Plasma Membrane ◽  
Apical Surface ◽  
Intracellular Traffic ◽  
Transmembrane Glycoprotein ◽  
Direct Demonstration ◽  
Targeting Signal

Glycosylation was considered the major signal candidate for apical targeting of transmembrane proteins in polarized epithelial cells. However, direct demonstration of the role of glycosylation has proved difficult because non-glycosylated apical transmembrane proteins usually do not reach the cell surface. Here we were able to follow the targeting of the apical transmembrane glycoprotein NPP3 both when glycosylated and non-glycosylated. Transfected in polarized MDCK and Caco-2 cells, NPP3 was exclusively expressed at the apical membrane. The transport kinetics of the protein to the cell surface were studied after metabolic (35)S-labeling and surface immunoprecipitation. The newly synthesized protein was mainly targeted directly to the apical surface in MDCK cells, whereas 50% transited through the basolateral surface in Caco-2 cells. In both cell types, the basolaterally targeted pool was effectively transcytosed to the apical surface. In the presence of tunicamycin, NPP3 was not N-glycosylated. The non-glycosylated protein was partially retained intracellularly but the fraction that reached the cell surface was nevertheless predominantly targeted apically. However, transcytosis of the non-glycosylated protein was partially impaired in MDCK cells. These results provide direct evidence that glycosylation cannot be considered an apical targeting signal for NPP3, although glycosylation is necessary for correct trafficking of the protein to the cell surface.

Changes in H+-translocating vacuolar-type ATPase in the anterior silk gland cell of Bombyx mori during metamorphosis.

1998 ◽  
Vol 201 (4) ◽  
pp. 479-486
Author(s):  
M Azuma ◽  
Y Ohta
Keyword(s):  
Bombyx Mori ◽  
Gland Cell ◽  
Specific Inhibitor ◽  
Instar Larva ◽  
Silk Gland ◽  
Ultrastructural Changes ◽  
Immunocytochemical Staining ◽  
Apical Plasma Membrane ◽  
Apical Surface ◽  
Silkworm Larvae

A proton-translocating vacuolar-type ATPase (V-ATPase) was identified and characterized in the anterior silk gland of Bombyx mori. By incubating the intact tissue with the fluorescent dye Acridine Orange, the acidified compartment was detected at the apical pole of the epithelial cells. This was observed throughout the feeding period of the fifth-instar larva until the onset of spinning. Acidification was prevented completely and reversibly by 0.8 micromol l-1 bafilomycin A1, a specific inhibitor of V-ATPase. The presence of V-ATPase in a microsomal fraction was verified by immunoblots using an antiserum to the V-ATPase holoenzyme from Manduca sexta midgut. The antiserum localized the V-ATPase to the apical plasma membrane of the anterior silk gland cells, suggesting that the enzyme is functionally active in pumping protons out of the cell towards the glandular lumen of feeding silkworm larvae. In spinning larvae, the acidification produced by the V-ATPase appears to cease, because acidic compartments were seen rarely and only in the periphery of basal cytoplasm, and because immunocytochemical staining for the V-ATPase was greatly reduced at the apical surface. The metamorphic changes in relation to the occurrence of V-ATPase corresponded well with the ultrastructural changes in the anterior silk gland cell of Bombyx mori larvae.

The transcytotic pathway of an apical plasma membrane protein (B10) in hepatocytes is similar to that of IgA and occurs via a tubular pericentriolar compartment

1996 ◽  
Vol 109 (6) ◽  
pp. 1215-1227 ◽  
Author(s):  
I. Hemery ◽  
A.M. Durand-Schneider ◽  
G. Feldmann ◽  
J.P. Vaerman ◽  
M. Maurice
Keyword(s):  
Electron Microscopy ◽  
Plasma Membrane ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Apical Membrane ◽  
Rat Hepatocytes ◽  
Apical Plasma Membrane ◽  
Apical Surface ◽  
Plasma Membrane Protein ◽  
Microtubule Disruption

In hepatocytes, newly synthesized apical plasma membrane proteins are first delivered to the basolateral surface and are supposed to reach the apical surface by transcytosis. The transcytotic pathway of apical membrane proteins and its relationship with other endosomal pathways has not been demonstrated morphologically. We compared the intracellular route of an apical plasma membrane protein, B10, with that of polymeric IgA (pIgA), which is transcytosed, transferrin (Tf) which is recycled, and asialoorosomucoid (ASOR) which is delivered to lysosomes. Ligands and anti-B10 monoclonal IgG were linked to fluorochromes or with peroxidase. The fate of each ligand was followed by confocal and electron microscopy in polarized primary monolayers of rat hepatocytes. When fluorescent anti-B10 IgG and fluorescent pIgA were simultaneously endocytosed for 15–30 minutes, they both uniformly labelled a juxtanuclear compartment. By 30–60 minutes, they reached the bile canaliculi. Tf and ASOR were also routed to the juxtanuclear area, but their fluorescence patterns were more punctate. Microtubule disruption prevented all ligands from reaching the juxtanuclear area. This area corresponded, at least partially, to the localization of the mannose 6-phosphate receptor, an endosomal marker. By electron microscopy, the juxtanuclear compartment was made up of anastomosing tubules connected to vacuoles, and was organized around the centrioles. B10 and pIgA were mainly found in the tubules, whereas ASOR was segregated inside the vacuolar elements and Tf within thinner, recycling tubules. In conclusion, transcytosis of the apical membrane protein B10 occurs inside tubules similar to those carrying pIgA, and involves passage via the pericentriolar area. In the pericentriolar area, the transcytotic tubules appear to maintain connections with other endosomal elements where sorting between recycled and degraded ligands occurs.

scholarly journals Neural Progenitor Cells Undergoing Yap/Tead-Mediated Enhanced Self-Renewal Form Heterotopias More Easily in the Diencephalon than in the Telencephalon

2018 ◽  
Vol 43 (1) ◽  
pp. 180-189 ◽  
Author(s):  
Kanako Saito ◽  
Ryotaro Kawasoe ◽  
Hiroshi Sasaki ◽  
Ayano Kawaguchi ◽  
Takaki Miyata
Keyword(s):  
Progenitor Cells ◽  
Neural Tube ◽  
Neural Progenitor Cells ◽  
Three Dimensional ◽  
Neural Progenitor ◽  
Hippo Signaling ◽  
Apical Surface ◽  
Elevated Expression ◽  
Underlying Mechanisms ◽  
The Brain

Abstract Spatiotemporally ordered production of cells is essential for brain development. Normally, most undifferentiated neural progenitor cells (NPCs) face the apical (ventricular) surface of embryonic brain walls. Pathological detachment of NPCs from the apical surface and their invasion of outer neuronal territories, i.e., formation of NPC heterotopias, can disrupt the overall structure of the brain. Although NPC heterotopias have previously been observed in a variety of experimental contexts, the underlying mechanisms remain largely unknown. Yes-associated protein 1 (Yap1) and the TEA domain (Tead) proteins, which act downstream of Hippo signaling, enhance the stem-like characteristics of NPCs. Elevated expression of Yap1 or Tead in the neural tube (future spinal cord) induces massive NPC heterotopias, but Yap/Tead-induced expansion of NPCs in the developing brain has not been previously reported to produce NPC heterotopias. To determine whether NPC heterotopias occur in a regionally characteristic manner, we introduced the Yap1-S112A or Tead-VP16 into NPCs of the telencephalon and diencephalon, two neighboring but distinct forebrain regions, of embryonic day 10 mice by in utero electroporation, and compared NPC heterotopia formation. Although NPCs in both regions exhibited enhanced stem-like behaviors, heterotopias were larger and more frequent in the diencephalon than in the telencephalon. This result, the first example of Yap/Tead-induced NPC heterotopia in the forebrain, reveals that Yap/Tead-induced NPC heterotopia is not specific to the neural tube, and also suggests that this phenomenon depends on regional factors such as the three-dimensional geometry and assembly of these cells.

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