Migration, early axonogenesis, and Reelin-dependent layer-forming behavior of early/posterior-born Purkinje cells in the developing mouse lateral cerebellum

Miyata, Takaki; Ono, Yūichi; Okamoto, Masakazu; Masaoka, Makoto; Sakakibara, Akira; Kawaguchi, Ayano; Hashimoto, Mitsuhiro; Ogawa, Michio

doi:10.1186/1749-8104-5-23

Cited by 105 publications

(112 citation statements)

References 71 publications

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“…We further demonstrate that reelin regulates the tangential migration of DA neurons by regulating their speed, trajectories and leading process orientation. These effects of reelin are consistent with some of its proposed functions during the migration of cortical projection neurons and cerebellar Purkinje cells (Britto et al, 2013;Miyata et al, 2010). Interestingly, in reelin pathway mutants, GIRK2 pos (primarily SN) and calbindin pos (primarily VTA) neurons are still largely split into lateral and medial clusters, respectively, indicating that reelin is not required for separating the two cell populations.…”

Section: Reelin Regulates Tangential Migration Of Da Neuronssupporting

confidence: 67%

Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system

et al. 2014

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The proper functioning of the dopaminergic system requires the coordinated formation of projections extending from dopaminergic neurons in the substantia nigra (SN), ventral tegmental area (VTA) and retrorubral field to a wide array of forebrain targets including the striatum, nucleus accumbens and prefrontal cortex. The mechanisms controlling the assembly of these distinct dopaminergic cell clusters are not well understood. Here, we have investigated in detail the migratory behavior of dopaminergic neurons giving rise to either the SN or the medial VTA using genetic inducible fate mapping, ultramicroscopy, time-lapse imaging, slice culture and analysis of mouse mutants. We demonstrate that neurons destined for the SN migrate first radially and then tangentially, whereas neurons destined for the medial VTA undergo primarily radial migration. We show that tangentially migrating dopaminergic neurons express the components of the reelin signaling pathway, whereas dopaminergic neurons in their initial, radial migration phase express CXC chemokine receptor 4 (CXCR4), the receptor for the chemokine CXC motif ligand 12 (CXCL12). Perturbation of reelin signaling interferes with the speed and orientation of tangentially, but not radially, migrating dopaminergic neurons and results in severe defects in the formation of the SN. By contrast, CXCR4/CXCL12 signaling modulates the initial migration of dopaminergic neurons. With this study, we provide the first molecular and functional characterization of the distinct migratory pathways taken by dopaminergic neurons destined for SN and VTA, and uncover mechanisms that regulate different migratory behaviors of dopaminergic neurons.

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Section: Reelin Regulates Tangential Migration Of Da Neuronssupporting

confidence: 67%

Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system

et al. 2014

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“…We were, however, intrigued that RELN was the most strongly downregulated gene in mutant SCA7 astrocytes. Reelin is primarily expressed in the brain and was originally characterized through its role in the direction of neuronal migration and positioning during development (14,28,29); however, it has also been shown to play a number of roles in the adult brain, including maintenance of the cerebellar PC layer and synaptic connections in the retina (16,30), modulation of neuronal glutamate receptor activity (31), direction of neuronal migration (14,32), and regulation of synaptic plasticity (33). Interestingly, the cerebellar pathology and general phenotype observed in RELN mutant mice are remarkably similar to those of transgenic SCA7 mice (4); yet, further studies would be needed to examine the role of polyQ ATXN7 during development, as well as the role of RELN deficiency in the maintenance of PCs in adults before a more substantial correlation could be made.…”

Section: Discussionmentioning

confidence: 99%

“…As a result, we sought to develop a tissue culture system with which we could characterize polyQ ATXN7-dependent alterations to gene expression and chromatin modification in human astrocytes that may contribute to noncell-autonomous neurodegeneration in SCA7. Here we characterize the association between expression of mutant ATXN7 and regulation of the reelin (RELN) gene, which plays a critical role in cerebellar development and PC maintenance (14)(15)(16), in a SCA7 astrocyte model.…”

mentioning

confidence: 99%

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

McCullough

Dent

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder that results from polyglutamine expansion of the ataxin-7 (ATXN7) protein. Remarkably, although mutant ATXN7 is expressed throughout the body, pathology is restricted primarily to the cerebellum and retina. One major goal has been to identify factors that contribute to the tissue specificity of SCA7. Here we describe the development and use of a human astrocyte cell culture model to identify reelin, a factor intimately involved in the development and maintenance of Purkinje cells and the cerebellum as a whole, as an ATXN7 target gene. We found that polyglutamine expansion decreased ATXN7 occupancy, which correlated with increased levels of histone H2B monoubiquitination, at the reelin promoter. Treatment with trichostatin A, but not other histone deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mutant ATXN7 into nuclear inclusions. Our findings suggest that reelin could be a previously unknown factor involved in the tissue specificity of SCA7 and that trichostatin A may ameliorate deleterious effects of the mutant ATXN7 protein by promoting its sequestration away from promoters into nuclear inclusions.chromatin | SAGA complex | histone modification A s a member of the polyglutamine expansion disorder family, Spinocerebellar ataxia type 7 (SCA7) is an autosomaldominant hereditary disease characterized by cerebellar and retinal degeneration eventually leading to death (1). Although the ataxin-7 (ATXN7) protein is expressed throughout the body, pathology is localized primarily within the cerebellum and retina. Cerebellar Purkinje cell (PC) degeneration is an integral step in the development and progression of SCA7 and has been observed in several independent transgenic mouse models of the disease (2-5); however, increasing evidence indicates that glial cell dysfunction contributes significantly to polyglutamine expansion disorder pathology (2, 6, 7). Interestingly, two distinct SCA7 mouse models exhibit non-cell-autonomous neurodegeneration (2, 4). Of these, the model used by Custer et al. (2) demonstrates that astrocyte-specific expression of polyQ ATXN7, via the Gfa2 promoter (8), results in PC degeneration and the onset of SCA7 symptoms. Astrocytes play a crucial role in the regulation of synaptic formation and function by ensheathing axon-dendrite connections to form a structure known as the tripartite synapse (9). This intimate interaction allows astrocytes to modulate synaptic function through the release of chemical messengers and the regulation of neurotransmitter and ion concentration within the synapse (9-11). The identification of tissue specificity factors and characterization of associated molecular mechanisms involved in their deregulation will facilitate a more comprehensive understanding of disease-associated events and advance efforts to develop effective treatments.The ATXN7 protein is an integral subunit of GCN5 (general control of amino acid synthesis-5; KAT2A)...

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“…Further work is required to identify the factors that regulate PC fate choice, cell-cycle progression and exit, differentiation (Zhao et al, 2007), migration (Goldowitz et al, 1997;Rice et al, 1998;Trommsdorff et al, 1999;Park and Curran, 2008), survival (e.g. Croci et al, 2006;Croci et al, 2011), axonogenesis (Sillitoe et al, 2009;Miyata et al, 2010) and dendritogenesis (Boukhtouche et al, 2006;Poulain et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Neurogenin 2 regulates progenitor cell-cycle progression and Purkinje cell dendritogenesis in cerebellar development

et al. 2012

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SUMMARYBy serving as the sole output of the cerebellar cortex, integrating a myriad of afferent stimuli, Purkinje cells (PCs) constitute the principal neuron in cerebellar circuits. Several neurodegenerative cerebellar ataxias feature a selective cell-autonomous loss of PCs, warranting the development of regenerative strategies. To date, very little is known as to the regulatory cascades controlling PC development. During central nervous system development, the proneural gene neurogenin 2 (Neurog2) contributes to many distinct neuronal types by specifying their fate and/or dictating development of their morphological features. By analyzing a mouse knock-in line expressing Cre recombinase under the control of Neurog2 cis-acting sequences we show that, in the cerebellar primordium, Neurog2 is expressed by cycling progenitors cell-autonomously fated to become PCs, even when transplanted heterochronically. During cerebellar development, Neurog2 is expressed in G1 phase by progenitors poised to exit the cell cycle. We demonstrate that, in the absence of Neurog2, both cell-cycle progression and neuronal output are significantly affected, leading to an overall reduction of the mature cerebellar volume. Although PC fate identity is correctly specified, the maturation of their dendritic arbor is severely affected in the absence of Neurog2, as null PCs develop stunted and poorly branched dendrites, a defect evident from the early stages of dendritogenesis. Thus, Neurog2 represents a key regulator of PC development and maturation.

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Migration, early axonogenesis, and Reelin-dependent layer-forming behavior of early/posterior-born Purkinje cells in the developing mouse lateral cerebellum

Cited by 105 publications

References 71 publications

Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system

Reelin and CXCL12 regulate distinct migratory behaviors during the development of the dopaminergic system

Reelin is a target of polyglutamine expanded ataxin-7 in human spinocerebellar ataxia type 7 (SCA7) astrocytes

Neurogenin 2 regulates progenitor cell-cycle progression and Purkinje cell dendritogenesis in cerebellar development

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