Intrauterine Growth Restriction Affects Cerebellar Granule Cells in the Developing Guinea Pig Brain

2018 ◽  
Vol 40 (2) ◽  
pp. 162-174 ◽  
Author(s):  
Mary Tolcos ◽  
Annie McDougall ◽  
Amy Shields ◽  
Yoonyoung Chung ◽  
Rachael O’Dowd ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Purkinje Cells ◽  
Granule Cell ◽  
Intrauterine Growth Restriction ◽  
Granular Layer ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Growth Restriction ◽  
Cerebellar Granule ◽  
Intrauterine Growth

Intrauterine growth restriction (IUGR) can lead to adverse neurodevelopmental sequelae in postnatal life. However, the effects of IUGR on the cerebellum are still to be fully elucidated. A major determinant of growth and development of the cerebellum is proliferation and subsequent migration of cerebellar granule cells. Our objective was to determine whether IUGR, induced by chronic placental insufficiency (CPI) in guinea pigs, results in abnormal cerebellar development due to deficits suggestive of impaired granule cell proliferation and/or migration. CPI was induced by unilateral ligation of the uterine artery at mid-gestation, producing growth-restricted (GR) foetuses at 52 and 60 days of gestation (dg), and neonates at 1 week postnatal age (term approx. 67 dg). Controls were from sham-operated animals. In GR foetuses compared with controls at 52 dg, the external granular layer (EGL) width and internal granular layer (IGL) area were similar. In GR foetuses compared with controls at 60 dg: (a) the EGL width was greater (p < 0.005); (b) the IGL area was smaller (p < 0.005); (c) the density of Ki67-negative (postmitotic) granule cells in the EGL was greater (p < 0.01); (d) the somal area of Purkinje cells was reduced (p < 0.005), and (e) the linear density of Bergmann glia was similar. The EGL width in GR foetuses at 60 dg was comparable to that of 52 dg control and GR foetuses. The pattern of p27-immunoreactivity in the EGL was the inverse of Ki67-immunoreactivity at both foetal ages; there was no difference between control and GR foetuses at either age in the width of p27-immunoreactivity, or in the percentage of the EGL width that it occupied. In the molecular layer of GR neonates compared with controls there was an increase in the areal density of granule cells (p < 0.05) and in the percentage of migrating to total number of granule cells (p < 0.01) at 1 week but not at 60 dg (p > 0.05). Thus, we found no specific evidence that IUGR affects granule cell proliferation, but it alters the normal program of migration to the IGL and, in addition, the development of Purkinje cells. Such alterations will likely affect the development of appropriate circuitry and have implications for cerebellar function.

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 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.

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 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.

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.

Cerebellar Granule Cells and Their Response to Radiation

1970 ◽  
Vol 28 ◽  
pp. 212-213
Author(s):  
Rosita F. de Estable-Puig ◽  
Juan F. Estable-Puig
Keyword(s):  
Cerebellar Cortex ◽  
Granular Layer ◽  
Granule Cells ◽  
Cerebellar Granule Cells ◽  
Mossy Fiber ◽  
Molecular Layer ◽  
Synaptic Connections ◽  
Cerebellar Granule ◽  
Peripheral Axon ◽  
Cerebellar Glomerulus

The granular layer of the cerebellar cortex situated between the molecular and medullary layers is built up mainly of the perikarya of small interneurons, the granule cells intermingled with part of their own processes, mossy fiber terminals, fibers of passage and other less numerous intrinsic cells. Ultrastructurally they are characterized by a nucleus which occupies most of the cell body and a rim of cytoplasm. The nucleus exhibits some aggregates of chromatin and in some cells a nucleolus. In the cytoplasm very scarce organelles are observed (Fig.l). Their main synaptic connections are found, first, at the cerebellar glomerulus where granule dendrites are seen in postsynaptic position towards mossy fiber rosettes. Desmosomic attachments are observed between granule dendrites. Second, at the level of the molecular layer where parallel fiber terminals (ramifications of the peripheral axon ) are seen apposing Purkinje dendrite spines.

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.

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