Distinct ankyrin isoforms at neuron cell bodies and nodes of Ranvier resolved using erythrocyte ankyrin-deficient mice.

Kordeli, Ekaterini; Bennett, Vann

doi:10.1083/jcb.114.6.1243

Cited by 118 publications

(72 citation statements)

References 40 publications

(62 reference statements)

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“…This specialization appears to have evolved from the tissue-specific, developmentally regulated expression of multiple protein isoforms. Ankyrin isoform diversity arises from different gene products, from differential, alternative splicing of the same gene product, from alternate polyadenylation, from the use of tissue-specific promoters, and/or the use of alternate NH 2 or COOH-termini [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Although numerous ankyrin-1 isoforms are visualized on Western blots of erythrocyte membranes [16], it is unknown if isoforms of ankyrin-1 are generated in erythroid cells by use of alternate translation initiation codons.…”

Section: Introductionmentioning

confidence: 99%

Ankyrin‐linked hereditary spherocytosis in an African–American kindred

et al. 2008

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Mutations of ankyrin-1 are the most frequent cause of the inherited hemolytic anemia, hereditary spherocytosis (HS), in people of European ancestry. Ankyrin-1, which provides the primary linkage between the erythrocyte membrane skeleton and the plasma membrane, has numerous isoforms generated by alternative splicing, alternate polyadenylation, use of tissue-specific promoters, and alternate NH 2 or COOH-termini. Mutation detection in erythrocyte membrane protein genes, including ankyrin, has been a challenge, primarily due to the large size of these genes, and the apparent frequent occurrence of HS-associated null alleles. Using denaturing high-performance liquid chromatography (DHPLC), we screened the ankyrin gene of the proband of a large, three generation African-American kindred with ankyrin-deficient HS. DHPLC yielded an abnormal chromatogram for exon 1. Examination of the corresponding exon 1 sequence in genomic DNA from the proband revealed heterozygosity for a mutation of the initiator methionine (ATG to ATA Met 1 Ile). Coupled in vitro transcription/translation studies with rabbit reticulocyte lysates demonstrated that the wild-type ankyrin erythroid cDNA initiates only from the known initiator methionine, indicating that the use of alternate initiator methionine is not a mechanism of isoform diversity in erythroid cells. The mutant ankyrin allele, unlike some initiator methionine mutations that utilize downstream codons for translation initiation, was associated with a null allele. This is the first report describing ankyrin-linked HS in an African-American kindred. Am. J. Hematol. 83:789-794, 2008. V

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Section: Introductionmentioning

confidence: 99%

Ankyrin‐linked hereditary spherocytosis in an African–American kindred

et al. 2008

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“…Resolution of the protein composition of these domains began with the discovery that both AIS and nodes of Ranvier are endowed with high local concentrations of voltage-gated sodium channels (VGSCs) (8). VGSCs copurified with membrane skeletal proteins, leading to the discovery that these channels associated directly and colocalized with the ankyrin family of membrane adaptors (9)(10)(11). The prototype ankyrin in erythrocytes couples the anion exchanger to a membrane-associated spectrin-actin network, suggesting the possibility of a similar function in stabilizing VGSC assemblies in the axon (12)(13)(14)(15).…”

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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.

149

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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“…The immunofluorescence localization of an ankyrin isoform to these sites supports a central role for this molecule in the formation and/or maintenance of such specialized membrane domains [52]. This isoform is not recognized by antibodies raised against ankyrin, or ankyrin, and is still present at normal levels in the nb mutation [48], suggesting that this isoform represents a third member of the ankyrin gene family expressed in nervous tissue.…”

Section: Ankyrinmentioning

confidence: 91%

“…Later studies have revealed that ankyrin, is also absent from the brain of these mice resulting in a neurodegenerative disorder [47]. These experiments, along with immunofluorescent studies using an antibody against the alternatively spliced exon discussed earlier, show that ankyrin, expression is limited to the plasma membrane of cell bodies and dendrites in specific neuronal populations in the rodent nervous system [48]. Expression in neurons of the cerebellum appears to be ubiquitous and the protein is seen in a large number of neurons in both the spinal cord and metencephalon.…”

Section: Ankyrinmentioning

confidence: 95%

From anemia to cerebellar dysfunction

Lambert

Bennett

1993

European Journal of Biochemistry

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The focus of this review is on the ankyrin gene family, key elements in the interaction of the spectrin-based membrane skeleton with the plasma membrane in a variety of tissues and multicellular organisms. The structure/function relationships of ankyrin molecules are reviewed, illustrating how these proteins are uniquely suited to serve as adaptors between the membrane skeleton and a number of integral membrane proteins. Advances in the understanding of ankyrin biology in the brain are discussed and used to show how ankyrins may be involved in the establishment and/or maintenance of specialized plasma membrane domains. Finally, recent research in hematological and neurological disorders are reviewed, suggesting that ankyrins have a role in the development of human disease.Perhaps the best characterized eukaryotic plasma membrane at the structural level is that of the human erythrocyte with its spectrin-based membrane skeleton. The skeleton consists of a filamentous network of structural proteins and is crucial to maintaining the shape and integrity of erythrocytes as these cells traverse the microcirculation [l]. The position of the skeleton, laminating the cytoplasmic surface of the lipid bilayer, also results in the restricted lateral diffusion of integral membrane proteins in the bilayer. This occurs either by a 'trapping' phenomenon, bought about by the limited ability of integral membrane proteins to traverse areas of the membrane 'fenced' in by the skeleton, or by the direct interaction of these proteins with components of the skeleton [2]. Since their first characterization in the human erythrocyte, identical or homologous components of the membrane skeleton have been identified in diverse cell types and tissues, ranging from Dictyostyliurn [3] to the mammalian brain [4].Concomitant with these findings has been the development of the concept of specialized domains of the plasma membrane. These regions of the cell arise from localized concentrations of specific integral proteins and are crucial to a multicellular existence. Such domains are utilized for a wide range of functions, from the establishment of cell-cell junctions to the complex integrative polarization events involved in the firing of a single Purkinje neuron. Development of specialized domains might well require the establishment of a sub-membrane structure capable of interacting with integral membrane proteins and allowing their targeting to and immobilization in defined regions of the cell. The spectrin membrane skeleton is a strong candidate for such an important structure with products of the ankyrin gene family The erythrocyte membrane skeletonThe erythrocyte membrane provides clues as to the organization of the spectrin skeleton and the role of ankyrins in other cellular systems. A number of extensive reviews have been written on the spectrin skeleton [6 -81 hence the subject will only be discussed briefly. The major component of the skeleton is spectrin, a flexible rod-shaped molecule with two subunits CI (Mr = 260000) and p (MI = 2250...

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Distinct ankyrin isoforms at neuron cell bodies and nodes of Ranvier resolved using erythrocyte ankyrin-deficient mice.

Cited by 118 publications

References 40 publications

Ankyrin‐linked hereditary spherocytosis in an African–American kindred

Ankyrin‐linked hereditary spherocytosis in an African–American kindred

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

From anemia to cerebellar dysfunction

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