Close homologue of adhesion molecule L1 promotes survival of Purkinje and granule cells and granule cell migration during murine cerebellar development

2009 ◽  
Vol 513 (5) ◽  
pp. 496-510 ◽  
Author(s):  
Igor Jakovcevski ◽  
Janina Siering ◽  
Gunnar Hargus ◽  
Nicole Karl ◽  
Laura Hoelters ◽  
...  
Keyword(s):  
Cell Migration ◽  
Adhesion Molecule ◽  
Granule Cell ◽  
Granule Cells ◽  
Cerebellar Development ◽  
Close Homologue

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.

The chemokine SDF1 regulates migration of dentate granule cells

Development ◽  
2002 ◽  
Vol 129 (18) ◽  
pp. 4249-4260 ◽  
Author(s):  
Anil Bagri ◽  
Theresa Gurney ◽  
Xiaoping He ◽  
Yong-Rui Zou ◽  
Dan R. Littman ◽  
...  
Keyword(s):  
Cell Migration ◽  
Dentate Gyrus ◽  
Granule Cell ◽  
Granule Cells ◽  
Ectopic Expression ◽  
Dentate Granule Cell ◽  
Vitro Assay ◽  
Dentate Granule Cells ◽  
Cell Position

The dentate gyrus is the primary afferent pathway into the hippocampus, but there is little information concerning the molecular influences that govern its formation. In particular, the control of migration and cell positioning of dentate granule cells is not clear. We have characterized more fully the timing and route of granule cell migration during embryogenesis using in utero retroviral injections. Using this information, we developed an in vitro assay that faithfully recapitulates important events in dentate gyrus morphogenesis. In searching for candidate ligands that may regulate dentate granule cell migration, we found that SDF1, a chemokine that regulates cerebellar and leukocyte migration, and its receptor CXCR4 are expressed in patterns that suggest a role in dentate granule cell migration. Furthermore, CXCR4 mutant mice have a defect in granule cell position. Ectopic expression of SDF1 in our explant assay showed that it directly regulates dentate granule cell migration. Our study shows that a chemokine is necessary for the normal development of the dentate gyrus, a forebrain structure crucial for learning and memory.

scholarly journals Deficits in Motor Coordination with Aberrant Cerebellar Development in Mice Lacking Testicular Orphan Nuclear Receptor 4

2005 ◽  
Vol 25 (7) ◽  
pp. 2722-2732 ◽  
Author(s):  
Yei-Tsung Chen ◽  
Loretta L. Collins ◽  
Hideo Uno ◽  
Chawnshang Chang
Keyword(s):  
Nuclear Receptor ◽  
Granule Cell ◽  
Motor Coordination ◽  
Granule Cells ◽  
Molecular Layer ◽  
Granule Cell Layer ◽  
Abnormal Development ◽  
Cerebellar Development ◽  
Morphological Development ◽  
Orphan Nuclear Receptor

ABSTRACT Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological function has remained largely unknown. Throughout postnatal development, TR4-knockout (TR4−/−) mice exhibited behavioral deficits in motor coordination, suggesting impaired cerebellar function. Histological examination of the postnatal TR4−/− cerebellum revealed gross abnormalities in foliation; specifically, lobule VII in the anterior vermis was missing. Further analyses demonstrated that the laminations of the TR4−/− cerebellar cortex were changed, including reductions in the thickness of the molecular layer and the internal granule layer, as well as delayed disappearance of the external granule cell layer (EGL). These lamination irregularities may result from interference with granule cell proliferation within the EGL, delayed inward migration of postmitotic granule cells, and a higher incidence of apoptotis. In addition, abnormal development of Purkinje cells was observed in the postnatal TR4−/− cerebellum, as evidenced by aberrant dendritic arborization and reduced calbindin staining intensity. Expression of Pax-6, Sonic Hedgehog (Shh), astrotactin (Astn), reelin, and Cdk-5, genes correlated with the morphological development of the cerebellum, is reduced in the developing TR4−/− cerebellum. Together, our findings suggest that TR4 is required for normal cerebellar development.

scholarly journals Immunoelectron microscopic localization of the neural cell adhesion molecules L1 and N-CAM during postnatal development of the mouse cerebellum.

1987 ◽  
Vol 105 (1) ◽  
pp. 569-576 ◽  
Author(s):  
E Persohn ◽  
M Schachner
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Granule Cell ◽  
Cell Adhesion Molecules ◽  
Granule Cells ◽  
Cell Types ◽  
Neural Cell ◽  
Neural Cell Adhesion Molecules ◽  
Neural Cell Adhesion

The cellular and subcellular localization of the neural cell adhesion molecules L1 and N-CAM was studied by pre- and postembedding immunoelectron microscopic labeling procedures in the developing mouse cerebellar cortex. The salient features of the study are: L1 displays a previously unrecognized restricted expression by particular neuronal cell types (i.e., it is expressed by granule cells but not by stellate and basket cells) and by particular subcellular compartments (i.e., it is expressed on axons but not on dendrites or cell bodies of Purkinje cells). L1 is always expressed on fasciculating axons and on postmitotic, premigratory, and migrating granule cells at sites of neuron-neuron contact, but never at contact sites between neuron and glia, thus strengthening the view that L1 is not involved in granule cell migration as a neuron-glia adhesion molecule. While N-CAM antibodies reacting with the three major components of N-CAM (180, 140, and 120 kD) show a rather uniform labeling of all cell types, antibodies to the 180-kD component (N-CAM180) stain only the postmigratory granule cell bodies supporting the notion that N-CAM180, the N-CAM component with the longest cytoplasmic domain, is not expressed before stable cell contacts are formed. Furthermore, N-CAM180 is only transiently expressed on Purkinje cell dendrites. N-CAM is present in synapses on both pre- and post-synaptic membranes. L1 is expressed only preterminally and not in the subsynaptic membranes. These observations indicate an exquisite degree of fine tuning in adhesion molecule expression during neural development and suggest a rich combinatorial repertoire in the specification of cell surface contacts.

scholarly journals Shp2 acts downstream of SDF-1α/CXCR4 in guiding granule cell migration during cerebellar development

2009 ◽  
Vol 334 (1) ◽  
pp. 276-284 ◽  
Author(s):  
Kazuki Hagihara ◽  
Eric E. Zhang ◽  
Yue-Hai Ke ◽  
Guofa Liu ◽  
Jan-Jan Liu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Granule Cell ◽  
Cerebellar Development

scholarly journals Effects of Phosphatidylserine Source of Docosahexaenoic Acid on Cerebellar Development in Preterm Pigs

2020 ◽  
Vol 10 (8) ◽  
pp. 475 ◽  
Author(s):  
Daniel Chizhikov ◽  
Randal K. Buddington ◽  
Igor Y. Iskusnykh
Keyword(s):  
Preterm Birth ◽  
Docosahexaenoic Acid ◽  
Purkinje Cells ◽  
Cognitive Processing ◽  
Granule Cell ◽  
Granule Cells ◽  
Cell Layer ◽  
Granule Cell Layer ◽  
Cerebellar Development ◽  
Control Group

Preterm birth, a major contributor to infant mortality and morbidity, impairs development of the cerebellum, the brain region involved in cognitive processing and motor function. Previously, we showed that at term-equivalent age, preterm pigs that received formula supplemented with docosahexaenoic acid (DHA) esterified to phosphatidylserine (PS) had cerebellar weights similar to those of newborn term pigs and were heavier than control preterm pigs. However, whether PS-DHA promotes the development of specific cerebellar cell populations or enhances key developmental processes remains unknown. Here we investigated the effects of the PS-DHA on development of the cerebellum in preterm pigs delivered via caesarean section and reared for ten days on a milk replacer with either PS-DHA (experimental group) or sunflower oil (control group). Upon necropsy, key cerebellar populations were analyzed using immunohistochemistry. Consumption of PS-DHA was associated with the expansion of undifferentiated granule cell precursors and increased proliferation in the external granule cell layer (EGL). Preterm pigs that received PS-DHA also had significantly fewer apoptotic cells in the internal granule cell layer (IGL) that contains differentiated granule neurons. PS-DHA did not affect the number of differentiating granule cells in the inner EGL, thickness of the inner EGL, density of Purkinje cells, or Bergmann glial fibers, or diameter of Purkinje cells. Thus, PS-DHA may support cerebellar development in preterm subjects by enhancing proliferation of granule cells, a process specifically inhibited by preterm birth, and increasing the survival of granule cells in the IGL. These findings suggest that PS-DHA is a promising candidate for clinical studies directed at enhancing brain development.

scholarly journals Sequential expression and differential function of multiple adhesion molecules during the formation of cerebellar cortical layers.

1987 ◽  
Vol 104 (2) ◽  
pp. 331-342 ◽  
Author(s):  
C M Chuong ◽  
K L Crossin ◽  
G M Edelman
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Granule Cell ◽  
Cell Adhesion Molecule ◽  
Granular Layer ◽  
Molecular Layer ◽  
External Granular Layer ◽  
Cortical Layers

We have correlated the times of appearance of the neural cell adhesion molecule (N-CAM), the neuron-glia cell adhesion molecule (Ng-CAM), and the extracellular matrix protein, cytotactin, during the development of the chicken cerebellar cortex, and have shown that these molecules make different functional contributions to granule cell migration. Immunofluorescent staining showed distinct spatiotemporal expression sequences for each adhesion molecule. N-CAM was present at all times in all layers. However, the large cytoplasmic domain polypeptide of N-CAM was always absent from the external granular layer and was enriched in the molecular layer as development proceeded. Ng-CAM began to be expressed in the premigratory granule cells just before migration and later disappeared from cell bodies but remained on parallel fibers. Cytotactin, which is synthesized by glia and not by neurons, appeared first in a speckled pattern within the external granular layer and later appeared in a continuous pattern along the Bergmann glia; it was also enriched in the molecular layer. After we established their order of appearance, we tested the separate functions of these adhesion molecules in granule cell migration by adding specific antibodies against each molecule to cerebellar explant cultures that had been labeled with tritiated thymidine and then measuring the differential distribution of labeled cells in the forming layers. Anti-N-CAM showed marginal effects. In contrast, anti-Ng-CAM arrested most cells in the external granular layer, while anti-cytotactin arrested most cells in the molecular layer. Time course analyses combined with sequential addition of different antibodies in different orders showed that anti-Ng-CAM had a major effect in the early period (first 36 h in culture) and a lesser effect in the second part of the culture period, while anti-cytotactin had essentially no effect at the earlier time but had major effects at a later period (18-72 h in culture). The two major stages of cerebellar granule cell migration thus appear to be differentially affected by distinct adhesion molecules of different cellular origins, binding mechanisms, and overall distributions. The results indicated that local cell surface modulation of adhesion molecules of different specificities at defined stages and sites is essential to the formation of cerebellar cortical layers.

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.

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