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.

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

Dysplastic gangliocytoma of cerebellum in a newborn

1984 ◽  
Vol 60 (4) ◽  
pp. 845-847 ◽  
Author(s):  
Uros Roessmann ◽  
Thamnook Wongmongkolrit
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Ganglion Cells ◽  
Cell Layer ◽  
Molecular Layer ◽  
Granule Cell Layer ◽  
Dysplastic Gangliocytoma ◽  
Content Type ◽  
External Granule Cell Layer ◽  
Fine Print

✓ Dysplastic gangliocytoma of the cerebellum is reported in a newborn. It is characterized by large ganglion cells in the molecular layer and premature attenuation of the external granule-cell layer. The internal granule-cell layer appears rarefied but otherwise normally organized. It appears that in this disease the migrating granule cells mature too early and become arrested in the molecular layer, because of their abnormal forms, while others continue to migrate and grow in size in their normal location in the inner granule-cell layer.

scholarly journals Deposition and role of thrombospondin in the histogenesis of the cerebellar cortex.

1990 ◽  
Vol 110 (4) ◽  
pp. 1275-1283 ◽  
Author(s):  
K S O'Shea ◽  
J S Rheinheimer ◽  
V M Dixit
Keyword(s):  
Cell Migration ◽  
Cerebellar Cortex ◽  
Granule Cell ◽  
Granule Cells ◽  
Cell Layer ◽  
Molecular Layer ◽  
Granule Cell Layer ◽  
External Granule Cell Layer ◽  
Dependent Inhibition ◽  
Cell Layers

The patterns of deposition of thrombospondin (TSP), a trimeric extracellular matrix glycoprotein, were determined during the initial establishment of the external granule cell layer and the subsequent inward migration of granule cells forming the molecular and (internal) granule cell layers. The early homogeneous deposition of TSP became restricted to the rhombic lip in the region of granule cell exit from the neuroepithelium, and was present between migrating granule cells. During the later inward migration of granule cells, little TSP was associated with dividing granule cells; it was enriched in premigratory granule cells. With the cessation of migration, TSP was lost except in association with fasciculating axons in the molecular layer where staining persisted briefly. At the EM level, TSP was associated with the leading process of granule cells as they associated with Bergmann glial cells and migrated through the molecular layer. TSP was present within granule cell axons; Purkinje cells and their dendrites, as well as Bergmann glial fibers and endfeet were negative for TSP. When anti-TSP antibodies were added to explant cultures of cerebellar cortex during active granule cell migration, a dose-dependent inhibition of migration was observed. In control cultures, granule cells migrated into the (internal) granule cell layer, while granule cells exposed to anti-TSP antibodies were arrested within the external granule cell layer. These results suggest that TSP plays an important role in the histogenesis of the cerebellar cortex by influencing granule cell migration.

Increased cell death and delayed development in the cerebellum of mice lacking the rev-erbA(alpha) orphan receptor

Development ◽  
2000 ◽  
Vol 127 (7) ◽  
pp. 1489-1498 ◽  
Author(s):  
P. Chomez ◽  
I. Neveu ◽  
A. Mansen ◽  
E. Kiesler ◽  
L. Larsson ◽  
...  
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Cell Layer ◽  
Orphan Receptor ◽  
Granule Cell Layer ◽  
External Granule Cell Layer ◽  
Alpha Gene ◽  
Cell Alterations ◽  
And Migration

The rev-erbA(alpha) gene, belonging to the steroid receptor superfamily of transcription factors, is highly conserved during evolution but little is known so far about its functions in development or in adult physiology. Here, we describe genetically altered mice lacking the rev-erbA(alpha) gene. These animals do not show any obvious phenotype in either fat tissue or skeletal muscle, despite the known regulation of rev-erbA(alpha) expression during adipocyte and myotube differentiation in vitro. However, during the second week of life, the cerebellum of rev-erbA(alpha) mutants presents several unexpected abnormalities, such as alterations in the development of Purkinje cells, delay in the proliferation and migration of granule cells from the external granule cell layer and increased apoptosis of neurons in the internal granule cell layer. Interestingly, the expression pattern of rev-erbA(alpha) suggests that the abnormalities observed in the external granule cell layer could be secondary to Purkinje cell alterations. Taken together, our data underline the importance of rev-erbA(alpha)expression for the appropriate balance of transcriptional activators and repressors during postnatal cerebellar development.

scholarly journals Genetic deletion of genes in the cerebellar rhombic lip lineage can stimulate compensation through adaptive reprogramming of ventricular zone-derived progenitors

2018 ◽  
Author(s):  
Alexandre Wojcinski ◽  
Morgane Morabito ◽  
Andrew K. Lawton ◽  
Daniel N. Stephen ◽  
Alexandra L. Joyner
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Ventricular Zone ◽  
Granule Cell Layer ◽  
Small Subset ◽  
Shh Signaling ◽  
Mouse Mutants ◽  
External Granule Cell Layer ◽  
Intrinsic Capacity ◽  
Developing Cerebellum

AbstractBackgroundThe cerebellum is a foliated posterior brain structure involved in coordination of motor movements and cognition. The cerebellum undergoes rapid growth postnataly due to Sonic Hedgehog (SHH) signaling-dependent proliferation of ATOH1+ granule cell precursors (GCPs) in the external granule cell layer (EGL), a key step for generating cerebellar foliation and the correct number of granule cells. Due to its late development, the cerebellum is particularly vulnerable to injury from preterm birth and stress around birth. We recently uncovered an intrinsic capacity of the developing cerebellum to replenish ablated GCPs via adaptive reprogramming of Nestin-expressing progenitors (NEPs). However, whether this compensation mechanism occurs in mouse mutants affecting the developing cerebellum and could lead to mis-interpretation of phenotypes was not known.MethodsWe used two different approaches to remove the main SHH signaling activator GLI2 in GCPs: 1) our mosaic mutant analysis with spatial and temporal control of recombination (MASTR) technique to deleteGli2in a small subset of GCPs; 2) AnAtohl-Cretransgene to deleteGli2in most of the EGL. Genetic Inducible Fate Mapping (GIFM) and live imaging were used to analyze the behavior of NEPs afterGli2deletion.ResultsMosaic analysis demonstrated that SHH-GLI2 signaling is critical for generating the correct pool of granule cells by maintaining GCPs in an undifferentiated proliferative state and promoting their survival. Despite this, inactivation ofGLI2in a large proportion of GCPs in the embryo did not lead to the expected dramatic reduction in the size of the adult cerebellum. GIFM uncovered that NEPs do indeed replenish GCPs inGli2conditional mutants, and then expand and partially restore the production of granule cells. Furthermore, the SHH signaling-dependent NEP compensation requiresGli2, demonstrating that the activator side of the pathway is involved.ConclusionWe demonstrate that a mouse conditional mutation that results in loss of SHH signaling in GCPs is not sufficient to induce long term severe cerebellum hypoplasia. The ability of the neonatal cerebellum to regenerate after loss of cells via a response by NEPs must therefore be considered when interpreting the phenotypes of conditional mutants affecting GCPs.

Altered synaptic transmission in dentate gyrus of rats reared in complex environments: evidence from hippocampal slices maintained in vitro

1986 ◽  
Vol 55 (4) ◽  
pp. 739-750 ◽  
Author(s):  
E. J. Green ◽  
W. T. Greenough
Keyword(s):  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Granule Cell ◽  
Granule Cells ◽  
Cell Layer ◽  
Molecular Layer ◽  
Hippocampal Slices ◽  
Granule Cell Layer ◽  
Complex Environments ◽  
Rearing Environment

Pre- and postsynaptic responses to activation of medial perforant path (MPP) axons were examined in hippocampal slices taken from rats reared for 3-4 wk in relatively complex (EC) or individual cage (IC) environments. Three types of extracellular field potentials were recorded in the infrapyramidal blade of the dentate gyrus: 1) granule cell population spikes (PSs), which reflect the number and synchrony of discharging granule cells (2), 2) population excitatory postsynaptic potentials (EPSPs), which reflect the amount of excitatory synaptic current flow into dendrites (28), and 3) presynaptic fiber volleys (FVs), which reflect the number of activated axons (28). Stimulation of the MPP evoked significantly larger PSs in slices taken from EC rats. There was no significant effect of rearing environment on PS/EPSP relationships. The slopes of EPSPs recorded at the site of synaptic activation in the dentate molecular layer and at the major current source in the dentate granule cell layer were significantly greater in slices taken from EC rats. The presynaptic FV was recorded at the site of synaptic activation in the molecular layer. FV amplitude did not differ significantly as a function of rearing environment. To examine possible differences in tissue impedance, granule cells were activated by stimulating granule cell axons in the dentate hilus and recording the antidromic PS in the granule cell layer. Antidromic PS amplitude was not significantly affected by rearing environment. The relative permanence of the experience-dependent alterations in synaptic transmission was assessed by comparing slices taken from rats that had been reared for 4 wk in complex environments followed by 3-4 wk in individual cages with those from rats reared for 7-8 wk in individual cages. There were no significant differences in MPP synaptic transmission between these groups of animals. The results suggest that experience in a relatively complex environment is associated with greater MPP synaptic transmission arising from an increased synaptic input to granule cells; the greater MPP synaptic transmission associated with behavioral experience can occur independent of behavioral state, influences from extrahippocampal brain regions and intrahippocampal inhibitory activity; and the experience-dependent synaptic alterations in the dentate gyrus are transient, in contrast to experience-dependent morphological alterations described in occipital cortex. The possible relationship of these alterations to the phenomenon of long-term enhancement is discussed.

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.

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.

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