AnkyrinG is required to maintain axo-dendritic polarity in vivo

Sobotzik, Jürgen-Markus; Sie, Jana Maria; Politi, Chrisoula; Turco, Domenico Del; Bennett, Vann; Deller, Thomas; Schultz, Christian

doi:10.1073/pnas.0909267106

Cited by 162 publications

(175 citation statements)

References 42 publications

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“…Previous studies of neuronal roles of AnkG in vivo have deleted all AnkG polypeptides in the postnatal cerebellum (17,18,26). To specifically examine the role of 480-kDa AnkG, we generated mice, with loxP sites flanking the giant exon, that were crossed with mice expressing Cre under control of the Nestin promoter in neuronal and glial precursors (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, AnkG promotes microtubule bundles and the submembrane material noted at the AIS by transmission electron microscopy (26). Consistent with these findings that multiple AIS proteins depend on AnkG, AnkG-null axons acquire dendritic properties in their proximal segments, both in cultured neurons as well as in mice (26,27). AnkG thus is a master organizer of the Significance Excitable axonal membrane microdomains are unique features of vertebrate nervous systems that are required for normal neuronal signaling and are involved in human neurological disorders.…”

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confidence: 99%

“…In a departure from the simple erythrocyte membrane, AnkG also directly interacts with and coordinates other components of the AIS, including a 186-kDa alternatively spliced variant of neurofascin, an L1 family cell adhesion molecule that directs GABAergic synapses to the AIS (17)(18)(19)(20)(21)(22), β4 spectrin, a member of the β-spectrin family that stabilizes the AIS and nodes of Ranvier (23,24), and KCNQ2/3 voltage-gated potassium channels that modulate sodium channel excitability (25). Moreover, AnkG promotes microtubule bundles and the submembrane material noted at the AIS by transmission electron microscopy (26). Consistent with these findings that multiple AIS proteins depend on AnkG, AnkG-null axons acquire dendritic properties in their proximal segments, both in cultured neurons as well as in mice (26,27).…”

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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.

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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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Section: Resultsmentioning

confidence: 99%

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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.

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222

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“…Both phenomena depend on ankG, because depletion of ankG results in the disappearance of AIS and the acquisition of dendritic identity by the proximal axon (11,12). However, the molecular role of ankG in the intracellular AIS organization is still unknown.…”

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confidence: 99%

“…However, the molecular role of ankG in the intracellular AIS organization is still unknown. The dependence of the AIS intracellular filter on ankG (10) and the disorganization of MT bundles in the AIS of Purkinje cells from ankG-deficient mice (12) suggest an unknown link between ankG and MTs in the AIS.…”

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confidence: 99%

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

Leterrier

Vacher

Fache

et al. 2011

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

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The axon initial segment (AIS) plays a key role in maintaining the molecular and functional polarity of the neuron. The relationship between the AIS architecture and the microtubules (MTs) supporting axonal transport is unknown. Here we provide evidence that the MT plus-end-binding (EB) proteins EB1 and EB3 have a role in the AIS in addition to their MT plus-end tracking protein behavior in other neuronal compartments. In mature neurons, EB3 is concentrated and stabilized in the AIS. We identified a direct interaction between EB3/EB1 and the AIS scaffold protein ankyrin G (ankG). In addition, EB3 and EB1 participate in AIS maintenance, and AIS disassembly through ankG knockdown leads to cell-wide up-regulation of EB3 and EB1 comets. Thus, EB3 and EB1 coordinate a molecular and functional interplay between ankG and the AIS MTs that supports the central role of ankG in the maintenance of neuronal polarity. N eurons are highly polarized cells that rely on microtubules (MTs) for maintenance of their architecture and long-range polarized trafficking (1). MTs supporting axonal transport travel through the axon initial segment (AIS), a compartment that is essential for the generation of action potentials (2) and the maintenance of neuronal polarity (3). Generation of action potentials depends on the concentration of voltage-gated sodium (Nav) and potassium channels at the AIS, which are tethered at the plasma membrane via their interaction with ankyrin G (ankG (4-7). ankG, in turn, is linked to the actin cytoskeleton via βIV-spectrin and organizes AIS formation by recruiting membrane proteins and βIV-spectrin to the nascent AIS (3).The AIS maintains neuronal polarity by forming a diffusion barrier for membrane constituents at the cell surface (4,8,9) and also by dampening intracellular diffusion and vesicular transport through the AIS (10). Both phenomena depend on ankG, because depletion of ankG results in the disappearance of AIS and the acquisition of dendritic identity by the proximal axon (11,12). However, the molecular role of ankG in the intracellular AIS organization is still unknown. The dependence of the AIS intracellular filter on ankG (10) and the disorganization of MT bundles in the AIS of Purkinje cells from ankG-deficient mice (12) suggest an unknown link between ankG and MTs in the AIS.The end-binding (EB) proteins family, composed of three members (EB1-3), has been described as plus-end-tracking proteins (+TIPs) that coordinate a network of dynamic proteins on the growing MT plus-ends (13). In neurons, EB1 has been implicated in axonal transport (14, 15), whereas EB3 has been characterized as a molecular link between MTs and the actin cytoskeleton (16, 17). We hypothesized that EB proteins could have a role in the AIS via interaction with the ankG/βIV-spectrin scaffold. We first found that EB3 is accumulated and stabilized in the AIS of mature neurons. Both EB3 and EB1 bind to ankG and participate in the maintenance of the AIS scaffold. Reciprocally, altering neuronal polarity through ankG knockdown in...

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Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case–control samples

Tesli

Koefoed

Athanasiu

et al. 2011

American J of Med Genetics Pt B

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Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case-control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case-control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case-control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.

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AnkyrinG is required to maintain axo-dendritic polarity in vivo

Abstract: axon initial segment ͉ axonal differentiation ͉ diffusion barrier ͉ cytoskeleton

Cited by 162 publications

References 42 publications

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

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

End-binding proteins EB3 and EB1 link microtubules to ankyrin G in the axon initial segment

Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case–control samples

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