SDF-1α induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells

Development ◽  
2001 ◽  
Vol 128 (11) ◽  
pp. 1971-1981 ◽  
Author(s):  
Robyn S. Klein ◽  
Joshua B. Rubin ◽  
Hilary D. Gibson ◽  
Elliot N. DeHaan ◽  
Xavier Alvarez-Hernandez ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cell Number ◽  
Calcium Flux ◽  
Neuronal Responses ◽  
And Migration ◽  
Activity Dependent

The chemokine SDF-1α (CXC12) and its receptor CXCR4 have been shown to play a role in the development of normal cerebellar cytoarchitecture. We report here that SDF-1α both induces chemotactic responses in granule precursor cells and enhances granule cell proliferative responses to Sonic hedgehog. Chemotactic and proliferative responses to SDF-1α are greater in granule cells obtained from cerebella of animals in the first postnatal week, coinciding with the observed in vivo peak in cerebellar CXCR4 expression. SDF-1α activation of neuronal CXCR4 differs from activation of CXCR4 in leukocytes in that SDF-1α-induced calcium flux is activity dependent, requiring predepolarization with KCl or pretreatment with glutamate. However, as is the case in leukocytes, neuronal responses to SDF-1α are all abolished by pretreatment of granule cells with pertussis toxin, suggesting they occur through Gαi activation. In conclusion, SDF-1α plays a role in two important processes of granule cell maturation – proliferation and migration – assisting in the achievement of appropriate cell number and position in the cerebellar cortex.

Cerebellar proteoglycans regulate sonic hedgehog responses during development

Development ◽  
2002 ◽  
Vol 129 (9) ◽  
pp. 2223-2232 ◽  
Author(s):  
Joshua B. Rubin ◽  
Yoojin Choi ◽  
Rosalind A. Segal
Keyword(s):  
Heparan Sulfate ◽  
Sonic Hedgehog ◽  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cell Layer ◽  
Heparan Sulfate Proteoglycans ◽  
Granule Cell Layer ◽  
Conserved Sequence ◽  
External Granule Cell Layer

Sonic hedgehog promotes proliferation of developing cerebellar granule cells. As sonic hedgehog is expressed in the cerebellum throughout life it is not clear why proliferation occurs only in the early postnatal period and only in the external granule cell layer. We asked whether heparan sulfate proteoglycans might regulate sonic hedgehog-induced proliferation and thereby contribute to the specialized proliferative environment of the external granule cell layer. We identified a conserved sequence within sonic hedgehog that is essential for binding to heparan sulfate proteoglycans, but not for binding to the receptor patched. Sonic hedgehog interactions with heparan sulfate proteoglycans promote maximal proliferation of postnatal day 6 granule cells. By contrast, proliferation of less mature granule cells is not affected by sonic hedgehog-proteoglycan interactions. The importance of proteoglycans for proliferation increases during development in parallel with increasing expression of the glycosyltransferase genes, exostosin 1 and exostosin 2. These data suggest that heparan sulfate proteoglycans, synthesized by exostosins, may be critical determinants of granule cell proliferation.

scholarly journals CEREBELLAR GRANULE CELLS IN VITRO

1970 ◽  
Vol 45 (2) ◽  
pp. 212-220 ◽  
Author(s):  
Fredrick J. Seil ◽  
Robert M. Herndon
Keyword(s):  
Granule Cell ◽  
Granular Layer ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Light And Electron Microscopy ◽  
Newborn Mouse ◽  
Newborn Mice ◽  
Cerebellar Cultures

The behavior of granule cells in mature cerebellar cultures derived from newborn mice was studied by light and electron microscopy. Many granule cells remained in the explants as an external granular layer. These cells were differentiated, as evidenced by formation of bundles of parallel fibers and by development of synapses between granule cell axons and Purkinje cell branchlet spines, and between Golgi cell axons and granule cell dendrites. Although the over-all architecture of the cerebellar explants after 18–33 days in vitro was similar to that of the newborn mouse, the evident differentiation of the granule cells suggested that interneuronal relationships resemble those of the mature cerebellum in vivo.

scholarly journals Synaptic representation of locomotion in single cerebellar granule cells

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Kate Powell ◽  
Alexandre Mathy ◽  
Ian Duguid ◽  
Michael Häusser
Keyword(s):  
Granule Cell ◽  
Synaptic Input ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Mossy Fiber ◽  
Input Layer ◽  
Rich Information ◽  
Synaptic Level ◽  
Single Granule

The cerebellum plays a crucial role in the regulation of locomotion, but how movement is represented at the synaptic level is not known. Here, we use in vivo patch-clamp recordings to show that locomotion can be directly read out from mossy fiber synaptic input and spike output in single granule cells. The increase in granule cell spiking during locomotion is enhanced by glutamate spillover currents recruited during movement. Surprisingly, the entire step sequence can be predicted from input EPSCs and output spikes of a single granule cell, suggesting that a robust gait code is present already at the cerebellar input layer and transmitted via the granule cell pathway to downstream Purkinje cells. Thus, synaptic input delivers remarkably rich information to single neurons during locomotion.

scholarly journals The Expression of the Cancer-Associated lncRNA Snhg15 Is Modulated by EphrinA5-Induced Signaling

2021 ◽  
Vol 22 (3) ◽  
pp. 1332
Author(s):  
Daniel Pensold ◽  
Julia Gehrmann ◽  
Georg Pitschelatow ◽  
Asa Walberg ◽  
Kai Braunsteffer ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Membrane Receptors ◽  
In Vitro Assays ◽  
Eph Receptor ◽  
Medulloblastoma Cell Line ◽  
And Migration

The Eph receptor tyrosine kinases and their respective ephrin-ligands are an important family of membrane receptors, being involved in developmental processes such as proliferation, migration, and in the formation of brain cancer such as glioma. Intracellular signaling pathways, which are activated by Eph receptor signaling, are well characterized. In contrast, it is unknown so far whether ephrins modulate the expression of lncRNAs, which would enable the transduction of environmental stimuli into our genome through a great gene regulatory spectrum. Applying a combination of functional in vitro assays, RNA sequencing, and qPCR analysis, we found that the proliferation and migration promoting stimulation of mouse cerebellar granule cells (CB) with ephrinA5 diminishes the expression of the cancer-related lncRNA Snhg15. In a human medulloblastoma cell line (DAOY) ephrinA5 stimulation similarly reduced SNHG15 expression. Computational analysis identified triple-helix-mediated DNA-binding sites of Snhg15 in promoters of genes found up-regulated upon ephrinA5 stimulation and known to be involved in tumorigenic processes. Our findings propose a crucial role of Snhg15 downstream of ephrinA5-induced signaling in regulating gene transcription in the nucleus. These findings could be potentially relevant for the regulation of tumorigenic processes in the context of glioma.

Role of Pax6 in development of the cerebellar system

Development ◽  
1999 ◽  
Vol 126 (16) ◽  
pp. 3585-3596 ◽  
Author(s):  
D. Engelkamp ◽  
P. Rashbass ◽  
A. Seawright ◽  
V. van Heyningen
Keyword(s):  
Cell Proliferation ◽  
Cell Migration ◽  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Long Distance ◽  
Cerebellar Granule ◽  
Precerebellar Nuclei ◽  
Rhombic Lip

Post-mitotic neurons generated at the rhombic lip undertake long distance migration to widely dispersed destinations, giving rise to cerebellar granule cells and the precerebellar nuclei. Here we show that Pax6, a key regulator in CNS and eye development, is strongly expressed in rhombic lip and in cells migrating away from it. Development of some structures derived from these cells is severely affected in Pax6-null Small eye (Pax6(Sey)/Pax6(Sey)) embryos. Cell proliferation and initial differentiation seem unaffected, but cell migration and neurite extension are disrupted in mutant embryos. Three of the five precerebellar nuclei fail to form correctly. In the cerebellum the pre-migratory granule cell sub-layer and fissures are absent. Some granule cells are found in ectopic positions in the inferior colliculus which may result from the complete absence of Unc5h3 expression in Pax6(Sey)/Pax6(Sey) granule cells. Our results suggest that Pax6 plays a strong role during hindbrain migration processes and at least part of its activity is mediated through regulation of the netrin receptor Unc5h3.

scholarly journals Deletion of Jdp2 enhances Slc7a11 expression in Atoh-1 positive cerebellum granule cell progenitors in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chia-Chen Ku ◽  
Kenly Wuputra ◽  
Kohsuke Kato ◽  
Jia-Bin Pan ◽  
Chia-Pei Li ◽  
...  
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Apoptotic Cell ◽  
Redox Homeostasis ◽  
Critical Role ◽  
Glutamate Transporter ◽  
Developmental Abnormalities ◽  
Oxidative Stresses

Abstract Background The cerebellum is the sensitive region of the brain to developmental abnormalities related to the effects of oxidative stresses. Abnormal cerebellar lobe formation, found in Jun dimerization protein 2 (Jdp2)-knockout (KO) mice, is related to increased antioxidant formation and a reduction in apoptotic cell death in granule cell progenitors (GCPs). Here, we aim that Jdp2 plays a critical role of cerebellar development which is affected by the ROS regulation and redox control. Objective Jdp2-promoter-Cre transgenic mouse displayed a positive signal in the cerebellum, especially within granule cells. Jdp2-KO mice exhibited impaired development of the cerebellum compared with wild-type (WT) mice. The antioxidation controlled gene, such as cystine-glutamate transporter Slc7a11, might be critical to regulate the redox homeostasis and the development of the cerebellum. Methods We generated the Jdp2-promoter-Cre mice and Jdp2-KO mice to examine the levels of Slc7a11, ROS levels and the expressions of antioxidation related genes were examined in the mouse cerebellum using the immunohistochemistry. Results The cerebellum of Jdp2-KO mice displayed expression of the cystine-glutamate transporter Slc7a11, within the internal granule layer at postnatal day 6; in contrast, the WT cerebellum mainly displayed Sla7a11 expression in the external granule layer. Moreover, development of the cerebellar lobes in Jdp2-KO mice was altered compared with WT mice. Expression of Slc7a11, Nrf2, and p21Cip1 was higher in the cerebellum of Jdp2-KO mice than in WT mice. Conclusion Jdp2 is a critical regulator of Slc7a11 transporter during the antioxidation response, which might control the growth, apoptosis, and differentiation of GCPs in the cerebellar lobes. These observations are consistent with our previous study in vitro.

scholarly journals Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum

2018 ◽  
Vol 115 (19) ◽  
pp. 5004-5009 ◽  
Author(s):  
Junsung Woo ◽  
Joo Ok Min ◽  
Dae-Si Kang ◽  
Yoo Sung Kim ◽  
Guk Hwa Jung ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Motor Performance ◽  
Neuronal Excitability ◽  
Motor Coordination ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Gaba Release ◽  
In Vivo Microdialysis ◽  
Tonic Inhibition

Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.

BDNF stimulates migration of cerebellar granule cells

Development ◽  
2002 ◽  
Vol 129 (6) ◽  
pp. 1435-1442 ◽  
Author(s):  
Paul R. Borghesani ◽  
Jean Michel Peyrin ◽  
Robyn Klein ◽  
Joshua Rubin ◽  
Alexandre R. Carter ◽  
...  
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cell Layer ◽  
Time Lapse ◽  
Granule Cell Layer ◽  
Boyden Chamber ◽  
Cerebellar Granule ◽  
Proliferative Zone ◽  
On Line

During development of the nervous system, neural progenitors arise in proliferative zones, then exit the cell cycle and migrate away from these zones. Here we show that migration of cerebellar granule cells out of their proliferative zone, the external granule cell layer (EGL), is impaired in Bdnf–/– mice. The reason for impaired migration is that BDNF directly and acutely stimulates granule cell migration. Purified Bdnf–/– granule cells show defects in initiation of migration along glial fibers and in Boyden chamber assays. This phenotype can be rescued by exogenous BDNF. Using time-lapse video microscopy we find that BDNF is acutely motogenic as it stimulates migration of individual granule cells immediately after addition. The stimulation of migration reflects both a chemokinetic and chemotactic effect of BDNF. Collectively, these data demonstrate that BDNF is directly motogenic for granule cells and provides a directional cue promoting migration from the EGL to the internal granule cell layer (IGL). Movies available on-line

Feedforward Inhibition Controls the Spread of Granule Cell–Induced Purkinje Cell Activity in the Cerebellar Cortex

2007 ◽  
Vol 97 (1) ◽  
pp. 248-263 ◽  
Author(s):  
Fidel Santamaria ◽  
Patrick G. Tripp ◽  
James M. Bower
Keyword(s):  
Cerebellar Cortex ◽  
Granule Cells ◽  
Functional Organization ◽  
Cerebellar Granule Cells ◽  
Molecular Layer ◽  
Cell Activity ◽  
Excitatory Input ◽  
Cortical Inhibition ◽  
Before And After

Synapses associated with the parallel fiber (pf) axons of cerebellar granule cells constitute the largest excitatory input onto Purkinje cells (PCs). Although most theories of cerebellar function assume these synapses produce an excitatory sequential “beamlike” activation of PCs, numerous physiological studies have failed to find such beams. Using a computer model of the cerebellar cortex we predicted that the lack of PCs beams is explained by the concomitant pf activation of feedforward molecular layer inhibition. This prediction was tested, in vivo, by recording PCs sharing a common set of pfs before and after pharmacologically blocking inhibitory inputs. As predicted by the model, pf-induced beams of excitatory PC responses were seen only when inhibition was blocked. Blocking inhibition did not have a significant effect in the excitability of the cerebellar cortex. We conclude that pfs work in concert with feedforward cortical inhibition to regulate the excitability of the PC dendrite without directly influencing PC spiking output. This conclusion requires a significant reassessment of classical interpretations of the functional organization of the cerebellar cortex.

In Vivo Intracellular Analysis of Granule Cell Axon Reorganization in Epileptic Rats

1999 ◽  
Vol 81 (2) ◽  
pp. 712-721 ◽  
Author(s):  
Paul S. Buckmaster ◽  
F. Edward Dudek
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Molecular Layer ◽  
Axon Collateral ◽  
Cell Axon ◽  
Recurrent Excitation ◽  
The Difference ◽  
Intracellular Analysis

In vivo intracellular analysis of granule cell axon reorganization in epileptic rats. In vivo intracellular recording and labeling in kainate-induced epileptic rats was used to address questions about granule cell axon reorganization in temporal lobe epilepsy. Individually labeled granule cells were reconstructed three dimensionally and in their entirety. Compared with controls, granule cells in epileptic rats had longer average axon length per cell; the difference was significant in all strata of the dentate gyrus including the hilus. In epileptic rats, at least one-third of the granule cells extended an aberrant axon collateral into the molecular layer. Axon projections into the molecular layer had an average summed length of 1 mm per cell and spanned 600 μm of the septotemporal axis of the hippocampus—a distance within the normal span of granule cell axon collaterals. These findings in vivo confirm results from previous in vitro studies. Surprisingly, 12% of the granule cells in epileptic rats, and none in controls, extended a basal dendrite into the hilus, providing another route for recurrent excitation. Consistent with recurrent excitation, many granule cells (56%) in epileptic rats displayed a long-latency depolarization superimposed on a normal inhibitory postsynaptic potential. These findings demonstrate changes, occurring at the single-cell level after an epileptogenic hippocampal injury, that could result in novel, local, recurrent circuits.

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