Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system

Zonta, Barbara; Tait, Steven; Melrose, Shona; Anderson, Heather; Harroch, Sheila; Higginson, Jennifer R.; Sherman, Diane L.; Brophy, Peter

doi:10.1083/jcb.200712154

Cited by 173 publications

(277 citation statements)

References 51 publications

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“…Two particularly interesting examples include the differential expression of neuronal and glial isoforms of Nfasc and Sgce genes (Zonta et al, 2008;Ritz et al, 2011), both of which are confirmed in our splicing database, among others. Next, to validate the accuracy of the novel cell type-specific splicing events in our dataset, we searched for a biologically significant gene candidate to validate via PCR.…”

Section: An Alternative Splicing Database Of Glia Neurons and Vascusupporting

confidence: 68%

An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex

et al. 2014

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The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function. To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from mouse cerebral cortex. We generated a transcriptome database for these eight cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain. For example, our data provide clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation attributable to unique splicing of PKM2, the gene encoding the glycolytic enzyme pyruvate kinase. This dataset will provide a powerful new resource for understanding the development and function of the brain. To ensure the widespread distribution of these datasets, we have created a user-friendly website (http://web.stanford.edu/group/barres_lab/ brain_rnaseq.html) that provides a platform for analyzing and comparing transciption and alternative splicing profiles for various cell classes in the brain.

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Section: An Alternative Splicing Database Of Glia Neurons and Vascusupporting

confidence: 68%

An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex

et al. 2014

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“…Our data do not allow us to distinguish whether Sh3tc2 is directly involved in the formation and/or maintenance of the node of Ranvier or whether the observed nodal widening is a secondary effect of hypomyelination. However, previous data show that disruption of the nodal gene Nfasc in the CNS results in a reduction of myelination, suggesting that the nodal phenotype could be the primary defect also in CMT4C (24). Moreover, our transcriptomic analysis revealed a 4-fold increase of expression of the nodal matrix gene Hapln2 already in 1-month-old Sh3tc2 ⌬Ex1/⌬Ex1 mice (Table S1), suggestive of the presence of early modifications in the nodal environment (25).…”

Section: Discussionmentioning

confidence: 52%

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

Arnaud¹,

Zenker

Charles³

et al. 2009

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

100

105

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Charcot–Marie–Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2 / KIAA1985 , was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2 Δ Ex1 /Δ Ex1 knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2 Δ Ex1 /Δ Ex1 animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2 Δ Ex1 /Δ Ex1 animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.

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“…30). In addition, other mechanisms participate in node assembly, including glial-derived extracellular matrix-mediated clustering of NF186, restriction of nodal protein mobility through a paranodal barrier, and stabilization of nodal proteins through interactions with the cytoskeleton (52,53).…”

Section: Resultsmentioning

confidence: 99%

Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling

Jenkins

Kim²,

Jones

et al. 2014

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

153

222

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Axon initial segments (AISs) and nodes of Ranvier are sites of clustering of voltage-gated sodium channels (VGSCs) in nervous systems of jawed vertebrates that facilitate fast long-distance electrical signaling. We demonstrate that proximal axonal polarity as well as assembly of the AIS and normal morphogenesis of nodes of Ranvier all require a heretofore uncharacterized alternatively spliced giant exon of ankyrin-G (AnkG). This exon has sequence similarity to I-connectin/Titin and was acquired after the first round of whole-genome duplication by the ancestral ANK2/ANK3 gene in early vertebrates before development of myelin. The giant exon resulted in a new nervous system-specific 480-kDa polypeptide combining previously known features of ANK repeats and β-spectrin-binding activity with a fibrous domain nearly 150 nm in length. We elucidate previously undescribed functions for giant AnkG, including recruitment of β4 spectrin to the AIS that likely is regulated by phosphorylation, and demonstrate that 480-kDa AnkG is a major component of the AIS membrane "undercoat' imaged by platinum replica electron microscopy. Surprisingly, giant AnkG-knockout neurons completely lacking known AIS components still retain distal axonal polarity and generate action potentials (APs), although with abnormal frequency. Giant AnkG-deficient mice live to weaning and provide a rationale for survival of humans with severe cognitive dysfunction bearing a truncating mutation in the giant exon. The giant exon of AnkG is required for assembly of the AIS and nodes of Ranvier and was a transformative innovation in evolution of the vertebrate nervous system that now is a potential target in neurodevelopmental disorders.neuropsychiatric disease | cognitive impairment disorder | axon initial segment | ankyrin-G | axonal polarity

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Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system

Cited by 173 publications

References 51 publications

An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex

An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling

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