Profilin1 activity in cerebellar granule neurons is required for radial migrationin vivo
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Neuron migration defects are an important aspect of human neuropathies. The underlying molecular mechanisms of such migration defects are largely unknown. Actin dynamics has been recognized as an important determinant of neuronal migration, and we recently found that the actin-binding protein profilin1 is relevant for radial migration of cerebellar granule neurons (CGN). As the exploited brain-specific mutants lacked profilin1 in both neurons and glial cells, it remained unknown whether profilin1 activity in CGN is relevant for CGN migration in vivo. To test this, we capitalized on a transgenic mouse line that expresses a tamoxifen-inducible Cre variant in CGN, but no other cerebellar cell type. In these profilin1 mutants, the cell density was elevated in the molecular layer, and ectopic CGN occurred. Moreover, 5-bromo-2′-deoxyuridine tracing experiments revealed impaired CGN radial migration. Hence, our data demonstrate the cell autonomous role of profilin1 activity in CGN for radial migration.Keywords:
Ectopic expression
Neuronal migration
During the embryonic development, neurons migrate from their origin to their final position. Control of neuronal migrations is critical for formation of the complex architecture of the central nervous system. In the developing central nervous system, there are two major patterns of neuronal migrations. One is radial migration and the other is tangential migration. In radial migration, migrating cells move along radial fibers that are processes of radial glial cells. Contact between radial glial cells and migrating cells has been supposed to control radial migration. In tangential migration, some tracts of neuronal migrations are controlled by chemokines. Neuronal migration utilizes its own migratory strategies, such as cell-cell contact with radial glial cells as well as common principles of cell migration like chemoattractants. As cell migrations reflect cytoskeletal changes in the cells, external cues like chemoattractants and cell adhesion finally influence the structure of cytoskeleton in migrating neurons. We summarize previous studies on cell migration and discuss specific mechanisms of neural migration in this review.
Neuronal migration
Neural cell
Neural Development
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Normal central nervous system development is dependent on extensive cell migration. Cells born in the proliferative ventricular zone migrate radially along specialized glial processes to their final locations. In contrast, most inhibitory interneurons found in the adult mammalian cerebral cortex and some other structures migrate along a nonradial pathway and on substrates only recently defined. Defects in radial cell migration have been implicated in several distinct human syndromes in which patients often present with epilepsy and mental retardation and have characteristic cerebral abnormalities. The identification of several genes responsible for human neural cell migration defects has led to a better understanding of the cellular and molecular interactions necessary for normal migration and the pathogenesis of these disorders. The prototypic cell migration disorder in humans is type I lissencephaly. Although type 1 lissencephaly is clearly a defect in radial cell migration, recent data from two model systems ( Lis1 and ARX mutant mice) indicate that a defect in non—radial cell migration also exists. Thus, the result of a LIS1 mutation appears to have broader implications than a radial cell migration defect alone. Furthermore, it is likely that the observed defect in non—radial cell migration contributes to the clinical phenotype observed in these patients. Herein we discuss the role of normal non—radial cell migration in cortical development, as well as how perturbations in both radial and nonradial migration result in developmental anomalies. ( J Child Neurol 2005;20:280—286).
Neuronal migration
Human brain
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Neuronal migration
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Neuronal migration
Neuroglia
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We study the coexistence of multiple periodic solutions for an analogue of the integrate-and-fire neuron model of two-neuron recurrent inhibitory loops with delayed feedback, which incorporates the firing process and absolute refractory period. Upon receiving an excitatory signal from the excitatory neuron, the inhibitory neuron emits a spike with a pattern-related delay, in addition to the synaptic delay. We present a theoretical framework to view the inhibitory signal from the inhibitory neuron as a self-feedback of the excitatory neuron with this additional delay. Our analysis shows that the inhibitory feedbacks with firing and the absolute refractory period can generate four basic types of oscillations, and the complicated interaction among these basic oscillations leads to a large class of periodic patterns and the occurrence of multistability in the recurrent inhibitory loop. We also introduce the average time of convergence to a periodic pattern to determine which periodic patterns have the potential to be used for neural information transmission and cognition processing in the nervous system.
Biological neuron model
Multistability
SIGNAL (programming language)
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Cross-correlation method was used for revealing effective inhibitory interactions in neural networks containing simultaneously recorded neurons from different loci of auditory cortex (A1) and medial geniculate body (MGB). It was shown that (i) inhibitory connections were "divergent", i. e., one neuron in A1 (MGB) depressed activity of neurons in different loci of A1 and MGB simultaneously; (ii) inputs to inhibitory neuron were "convergent", i.e., one neuron in A1 (MGB) was excited by neurons from different loci of A1 and MGB simultaneously. There were inhibitory neurons which selectively depressed activity of only one neighbouring neuron. The results allow to suggest that the same inhibitory neuron may be involved in afferent and feedback inhibition. We supposed that the principles of organization of inhibitory connections in thalamo-cortical networks underlie the observed exceptions to mapping (tonotopic) principle of organization of receptive fields of A1 and MGB.
Medial geniculate body
Tonotopy
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In computational neural network models, neurons are usually allowed to excite some and inhibit other neurons, depending on the weight of their synaptic connections. The traditional way to transform such networks into networks that obey Dale's law (i.e., a neuron can either excite or inhibit) is to accompany each excitatory neuron with an inhibitory one through which inhibitory signals are mediated. However, this requires an equal number of excitatory and inhibitory neurons, whereas a realistic number of inhibitory neurons is much smaller. In this letter, we propose a model of nonlinear interaction of inhibitory synapses on dendritic compartments of excitatory neurons that allows the excitatory neurons to mediate inhibitory signals through a subset of the inhibitory population. With this construction, the number of required inhibitory neurons can be reduced tremendously.
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Normal central nervous system development is dependent on extensive cell migration. Cells born in the proliferative ventricular zone migrate radially along specialized glial processes to their final locations. In contrast, most inhibitory interneurons found in the adult mammalian cerebral cortex and some other structures migrate along a nonradial pathway and on substrates only recently defined. Defects in radial cell migration have been implicated in several distinct human syndromes in which patients often present with epilepsy and mental retardation and have characteristic cerebral abnormalities. The identification of several genes responsible for human neural cell migration defects has led to a better understanding of the cellular and molecular interactions necessary for normal migration and the pathogenesis of these disorders. The prototypic cell migration disorder in humans is type I lissencephaly. Although type 1 lissencephaly is clearly a defect in radial cell migration, recent data from two model systems ( Lis1 and ARX mutant mice) indicate that a defect in non—radial cell migration also exists. Thus, the result of a LIS1 mutation appears to have broader implications than a radial cell migration defect alone. Furthermore, it is likely that the observed defect in non—radial cell migration contributes to the clinical phenotype observed in these patients. Herein we discuss the role of normal non—radial cell migration in cortical development, as well as how perturbations in both radial and nonradial migration result in developmental anomalies. ( J Child Neurol 2005;20:280—286).
Neuronal migration
Human brain
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In the developing brain the majority of neurons migrate from their birthplace to their final destination. This active movement is essential for the formation of cortical layers and nuclei. The impairment of migration does not affect the viability of neurons but often results in abnormal differentiation. The proper migration of neurons requires the orchestrated activities of multiple cellular and molecular events, such as pathway selection, the activation of specific receptors and channels, and the assembly and disassembly of cytoskeletal components. The migration of neurons is very vulnerable to exposure to environmental toxins, such as alcohol. In this article, we will focus on recent developments in the migration of cerebellar granule cells. First, we will describe when, where and how granule cells migrate through different cortical layers to reach their final destination. Second, we will present how internal programs control the sequential changes in granule cell migration. Third, we will review the roles of external guidance cues and transmembrane signals in granule cell migration. Finally, we will reveal mechanisms by which alcohol exposure impairs granule cell migration.
Granule cell
Granule (geology)
Neuronal migration
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A fundamental feature of brain development is the migration of neurons from their place of birth to the location where they will assemble and integrate into a neural circuit. We have recently reported that one facial branchiomotor neuron (FBMN) can influence the migration of another FBMN, defining this cell movement as a collective migration. As with any collective migration, cell‐to‐cell contact is required for one cell's influence on another. To determine if this was the case, we imaged the migration of membrane‐mCherry‐expressing FBMNs in live zebrafish embryos. We find that some neurons display persistent, sustained migration in one direction (posterior), whereas other FBMNs stall for short periods of time. We noticed that FBMNs stalled in migration shortly after cell‐to‐cell contact with neuron in their migratory path. This is reminiscent of contact inhibition of locomotion (CIL) observed for many other cell types including neural crest cells. We therefore, quantified the speed and direction of neuron movement before and after neuron‐to‐neuron cell contacts. Consistent with this, centrosomes, which often re‐orient in the direction of migration, were often found on the anterior side of migrating FBMNs. Previous work has shown that planar cell polarity (PCP) genes are essential for FBMN migration. Here we show that PCP mutant neurons migrate in random directions suggesting that PCP proteins are not required for migration per se, but are required for persistent directed movements. Taken together these data suggest the possibility that PCP proteins control contact‐dependent cell polarization in FBMN migration.
Cell polarity
Border cells
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