scholarly journals Cerebellar granule cells are predominantly generated by terminal symmetric divisions of granule cell precursors

2015 ◽  
Vol 244 (6) ◽  
pp. 748-758 ◽  
Author(s):  
Kie Nakashima ◽  
Hiroki Umeshima ◽  
Mineko Kengaku
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cerebellar Granule ◽  
Granule Cell Precursors

scholarly journals Cerebellar granule cell precursors can extend processes, undergo short migratory movements and express postmitotic markers before mitosis in the chick EGL

2017 ◽  
Author(s):  
Michalina Hanzel ◽  
Richard JT Wingate
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cerebellar Granule Cell ◽  
In Ovo ◽  
Differentiation Markers ◽  
Fixed Tissue ◽  
Cerebellar Granule ◽  
Sequence Of Events ◽  
Granule Cell Precursors

Cerebellar granule cell precursors (GCPs) form a secondary germinative epithelium, the external germinal layer (EGL) where they proliferate extensively to produce the most numerous cell type in the brain. The morphological sequence of events that characterizes the differentiation of GCPs in the EGL is well established. However, morphologies of individual GCP and their differentiation status have never been correlated. Here, we examine the morphological features and transitions of GCPs in the chicken cerebellum by labelling a subset of GCPs with a stable genomic expression of a GFP transgene and following their development within the EGL in fixed tissue and using time-lapse imaging. We use immunohistochemistry to observe cellular morphologies of mitotic and differentiating GCPs to better understand their differentiation dynamics. Results reveal that mitotic activities of GCPs are more complex and dynamic than currently appreciated. While most GCPs divide in the outer and middle EGL, some are capable of division in the inner EGL. Some GCPs remain mitotically active during process extension and tangential migration and retract their processes prior to each cell division. The mitotically active precursors can also express differentiation markers such as TAG1 and NeuroD1. Further, we explore the result of misexpression of NeuroD1 on granule cell development. When misexpressed in GCPs, NeuroD1 leads to premature differentiation, defects in migration and reduced cerebellar size and foliation. Overall, we provide the first characterisation of individual morphologies of mitotically active cerebellar GCPs in ovo and reaffirm the role of NeuroD1 as a differentiation factor in the development of cerebellar granule cells.

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.

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

scholarly journals Cerebellar granule cells contain a membrane mitogen for cultured Schwann cells.

1989 ◽  
Vol 108 (2) ◽  
pp. 607-611 ◽  
Author(s):  
P W Mason ◽  
J W Bigbee ◽  
G H DeVries
Keyword(s):  
Cell Proliferation ◽  
Schwann Cell ◽  
Schwann Cells ◽  
Cell Cultures ◽  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Proteoglycan Synthesis ◽  
Cerebellar Granule ◽  
Mitogenic Signal

Proliferation of Schwann cells is one of the first events that occurs after contact with a growing axon. To further define the distribution and properties of this axonal mitogen, we have (a) cocultured cerebellar granule cells, which lack glial ensheathment in vivo with Schwann cells; and (b) exposed Schwann cell cultures to isolated granule cell membranes. Schwann cells cocultured with granule cells had a 30-fold increase in the labeling index over Schwann cells cultured alone, suggesting that the mitogen is located on the granule cell surface. Inhibition of granule cell proteoglycan synthesis caused a decrease in the granule cells' ability to stimulate Schwann cell proliferation. Membranes isolated from cerebellar granule cells when added to Schwann cell cultures caused a 45-fold stimulation in [3H]thymidine incorporation. The granule cell mitogenic signal was heat and trypsin sensitive and did not require lysosomal processing by Schwann cells to elicit its proliferative effect. The ability of granule cells and their isolated membranes to stimulate Schwann cell proliferation suggests that the mitogenic signal for Schwann cells is a ubiquitous factor present on all axons regardless of their ultimate state of glial ensheathment.

scholarly journals Recent advances in understanding the mechanisms of cerebellar granule cell development and function and their contribution to behavior

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1142 ◽  
Author(s):  
Elizabeth P. Lackey ◽  
Detlef H. Heck ◽  
Roy V. Sillitoe
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Expression Patterns ◽  
Cell Lineage ◽  
Autism Spectrum ◽  
Cerebellar Granule ◽  
Motor Behaviors ◽  
Recent Advances ◽  
And Function

The cerebellum is the focus of an emergent series of debates because its circuitry is now thought to encode an unexpected level of functional diversity. The flexibility that is built into the cerebellar circuit allows it to participate not only in motor behaviors involving coordination, learning, and balance but also in non-motor behaviors such as cognition, emotion, and spatial navigation. In accordance with the cerebellum’s diverse functional roles, when these circuits are altered because of disease or injury, the behavioral outcomes range from neurological conditions such as ataxia, dystonia, and tremor to neuropsychiatric conditions, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. Two major questions arise: what types of cells mediate these normal and abnormal processes, and how might they accomplish these seemingly disparate functions? The tiny but numerous cerebellar granule cells may hold answers to these questions. Here, we discuss recent advances in understanding how the granule cell lineage arises in the embryo and how a stem cell niche that replenishes granule cells influences wiring when the postnatal cerebellum is injured. We discuss how precisely coordinated developmental programs, gene expression patterns, and epigenetic mechanisms determine the formation of synapses that integrate multi-modal inputs onto single granule cells. These data lead us to consider how granule cell synaptic heterogeneity promotes sensorimotor and non-sensorimotor signals in behaving animals. We discuss evidence that granule cells use ultrafast neurotransmission that can operate at kilohertz frequencies. Together, these data inspire an emerging view for how granule cells contribute to the shaping of complex animal behaviors.

scholarly journals Overlapping functions of the cell adhesion molecules Nr-CAM and L1 in cerebellar granule cell development

2001 ◽  
Vol 154 (6) ◽  
pp. 1259-1274 ◽  
Author(s):  
Takeshi Sakurai ◽  
Marc Lustig ◽  
Joanne Babiarz ◽  
Andrew J.W. Furley ◽  
Steven Tait ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Granule Cell ◽  
Cell Adhesion Molecules ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Cell Development ◽  
Cerebellar Granule Cell ◽  
Granule Cell Layer ◽  
Cerebellar Granule

The structurally related cell adhesion molecules L1 and Nr-CAM have overlapping expression patterns in cerebellar granule cells. Here we analyzed their involvement in granule cell development using mutant mice. Nr-CAM–deficient cerebellar granule cells failed to extend neurites in vitro on contactin, a known ligand for Nr-CAM expressed in the cerebellum, confirming that these mice are functionally null for Nr-CAM. In vivo, Nr-CAM–null cerebella did not exhibit obvious histological defects, although a mild size reduction of several lobes was observed, most notably lobes IV and V in the vermis. Mice deficient for both L1 and Nr-CAM exhibited severe cerebellar folial defects and a reduction in the thickness of the inner granule cell layer. Additionally, anti-L1 antibodies specifically disrupted survival and maintenance of Nr-CAM–deficient granule cells in cerebellar cultures treated with antibodies. The combined results indicate that Nr-CAM and L1 play a role in cerebellar granule cell development, and suggest that closely related molecules in the L1 family have overlapping functions.

scholarly journals REDUNDANT MYELIN SHEATHS AND OTHER ULTRASTRUCTURAL FEATURES OF THE TOAD CEREBELLUM

1966 ◽  
Vol 28 (1) ◽  
pp. 73-93 ◽  
Author(s):  
Jack Rosenbluth
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Second Phase ◽  
Full Thickness ◽  
Cerebellar Granule ◽  
Myelin Sheaths ◽  
Ultrastructural Cytology ◽  
Two Phases ◽  
General Organization

Some of the myelin sheaths in the cerebellum of normal adult toads exhibit extensive evaginations of their full thickness. These redundant flaps of myelin are collapsed; i.e., they contain no axon and have no lumen. They extend away from the parent axonal myelin sheaths and tend to enfold other myelinated fibers or granule cell perikarya, producing bizarre configurations of myelin and what appear to be partially or completely myelinated cell bodies. In some instances, only the redundant flap of myelin appears in the plane of section, and its attachment to an axonal myelin sheath in another plane is only inferred. Single lamellae of myelin also tend to invest cerebellar granule cells and other processes, and these too appear to fold on themselves producing two- or four-layered segments. It is suggested that there are two phases of myelinogenesis: an initial "wrapping" phase, followed by a prolonged second phase during which internodes of myelin increase in both length and girth by a process other than wrapping, and that the occurrence of redundant myelin sheaths may reflect overgrowth of myelin during the second phase. Observations on the general organization of the toad cerebellum and on the ultrastructural cytology of its layers are also presented.

Ionic Mechanism of Electroresponsiveness in Cerebellar Granule Cells Implicates the Action of a Persistent Sodium Current

1998 ◽  
Vol 80 (2) ◽  
pp. 493-503 ◽  
Author(s):  
Egidio D'Angelo ◽  
Giovanna De Filippi ◽  
Paola Rossi ◽  
Vanni Taglietti
Keyword(s):  
Action Potential ◽  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Sodium Current ◽  
Ionic Mechanism ◽  
Persistent Sodium Current ◽  
Spike Discharge ◽  
Cerebellar Granule ◽  
Voltage Dependent

D'Angelo, Egidio, Giovanna De Filippi, Paola Rossi, and Vanni Taglietti. Ionic mechanism of electroresponsiveness in cerebellar granule cells implicates the action of a persistent sodium current. J. Neurophysiol. 80: 493–503, 1998. Although substantial knowledge has been accumulated on cerebellar granule cell voltage-dependent currents, their role in regulating electroresponsiveness has remained speculative. In this paper, we have used patch-clamp recording techniques in acute slice preparations to investigate the ionic basis of electroresponsiveness of rat cerebellar granule cells at a mature developmental stage. The granule cell generated a Na+-dependent spike discharge resistant to voltage and time inactivation, showing a linear frequency increase with injected currents. Action potentials arose when subthreshold depolarizing potentials, which were driven by a persistent Na+ current, reached a critical threshold. The stability and linearity of the repetitive discharge was based on a complex mechanism involving a N-type Ca2+ current blocked by ω-CTx GVIA, and a Ca2+-dependent K+ current blocked by charibdotoxin and low tetraethylammonium (TEA; <1 mM); a voltage-dependent Ca2+-independent K+ current blocked by high TEA (>1 mM); and an A current blocked by 2 mM 4-aminopyridine. Weakening TEA-sensitive K+ currents switched the granule cell into a bursting mode sustained by the persistent Na+ current. A dynamic model is proposed in which the Na+ current-dependent action potential causes secondary Ca2+ current activation and feedback voltage- and Ca2+-dependent afterhyperpolarization. The afterhyperpolarization reprimes the channels inactivated in the spike, preventing adaptation and bursting and controlling the duration of the interspike interval and firing frequency. This result reveals complex dynamics behind repetitive spike discharge and suggests that a persistent Na+ current plays an important role in action potential initiation and in the regulation of mossy fiber-granule cells transmission.

Synaptic Activation of Ca2+ Action Potentials in Immature Rat Cerebellar Granule Cells In Situ

1997 ◽  
Vol 78 (3) ◽  
pp. 1631-1642 ◽  
Author(s):  
Egidio D'Angelo ◽  
Giovanna De Filippi ◽  
Paola Rossi ◽  
Vanni Taglietti
Keyword(s):  
Nmda Receptor ◽  
Granule Cell ◽  
Action Potentials ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Synaptic Activation ◽  
Immature Rat ◽  
Cerebellar Granule ◽  
Channel Dependent

D'Angelo, Egidio, Giovanna De Filippi, Paola Rossi, and Vanni Taglietti. Synaptic activation of Ca2+ action potentials in immature rat cerebellar granule cells in situ. J. Neurophysiol. 78: 1631–1642, 1997. Although numerous Ca2+ channels have been identified in cerebellar granule cells, their role in regulating excitability remained unclear. We therefore investigated the excitable response in granule cells using whole cell patch-clamp recordings in acute rat cerebellar slices throughout the time of development (P4–P21, n = 183), with the aim of identifying the role of Ca2+ channels and their activation mechanism. After depolarizing current injection, 46% of granule cells showed Ca2+ action potentials, whereas repetitive Na+ spikes were observed in an increasing proportion of granule cells from P4 to P21. Because Ca2+ action potentials were no longer observed after P21, they characterized an immature granule cell functional stage. Ca2+ action potentials consisted of an intermediate-threshold spike (ITS) activating at −60/−50 mV and sensitive to voltage inactivation and of a high-threshold spike (HTS), activating at above −30 mV and resistant to voltage inactivation. Both ITS and HTS comprised transient and protracted Ca2+ channel-dependent depolarizations. The Ca2+ action potentials could be activated synaptically by excitatory postsynaptic potentials, which were significantly slower and had a proportionately greater N-methyl-d-aspartate (NMDA) receptor-mediated component than those recorded in cells with fast repetitive Na+ spikes. The NMDA receptor current, by providing a sustained and regenerative current injection, was critical for activating the ITS, which was not self-regenerative. Moreover, NMDA receptors determined temporal summation of impulses during repetitive mossy fiber transmission, raising membrane potential into the range required for generating protracted Ca2+ channel-dependent depolarizations. The nature of Ca2+ action potentials was considered further using selective ion channel blockers. N-, L-, and P-type Ca2+ channels generated protracted depolarizations, whereas the ITS and HTS transient phase was generated by putative R-type channels (RITS and RHTS, respectively). RHTS channels had a higher activation threshold and were more resistant to voltage inactivation than RITS channels. At a mature stage, most of the Ca2+-dependent effects depended on the N-type current, which promoted spike repolarization and regulated the Na+-dependent discharge frequency. These observations relate Ca2+ channel types with specific neuronal excitable properties and developmental states in situ. Synaptic NMDA receptor-dependent activation of Ca2+ action potentials provides a sophisticated mechanism for Ca2+ signaling, which might be involved in granule cell development and plasticity.

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