Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Hill, Jennifer K.; Williams, Diane E.; LeMasurier, Meredith; Dumont, Rachel A.; Strehler, Emanuel E.; Gillespie, Peter G.

doi:10.1523/jneurosci.0447-06.2006

Cited by 68 publications

(74 citation statements)

References 58 publications

(80 reference statements)

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“…Of phalloidin-positive structures, 50% (27/54) from cochlear progenitors and 73% (58/79) from vestibular progenitors were immunoreactive for plasma membrane Ca 2+ -ATPase 2 (PMCA2; also known as Atp2b2; Fig. 2C,H), which is abundant in postnatal HC bundles (Chen et al, 2012;Dumont et al, 2001;Hill et al, 2006). PMCA2-like immunoreactivity was strong at the base of the actin-positive structures (Fig.…”

Section: Hc Proteins In Cells Differentiated From Inner Ear Progenitorsmentioning

confidence: 99%

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

McLean

Eatock

et al. 2016

Development

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Disorders of hearing and balance are most commonly associated with damage to cochlear and vestibular hair cells or neurons. Although these cells are not capable of spontaneous regeneration, progenitor cells in the hearing and balance organs of the neonatal mammalian inner ear have the capacity to generate new hair cells after damage. To investigate whether these cells are restricted in their differentiation capacity, we assessed the phenotypes of differentiated progenitor cells isolated from three compartments of the mouse inner ear -the vestibular and cochlear sensory epithelia and the spiral ganglion -by measuring electrophysiological properties and gene expression. Lgr5 + progenitor cells from the sensory epithelia gave rise to hair cell-like cells, but not neurons or glial cells. Newly created hair cell-like cells had hair bundle proteins, synaptic proteins and membrane proteins characteristic of the compartment of origin. PLP1 + glial cells from the spiral ganglion were identified as neural progenitors, which gave rise to neurons, astrocytes and oligodendrocytes, but not hair cells. Thus, distinct progenitor populations from the neonatal inner ear differentiate to cell types associated with their organ of origin.

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Section: Hc Proteins In Cells Differentiated From Inner Ear Progenitorsmentioning

confidence: 99%

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

McLean

Eatock

et al. 2016

Development

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“…Examples include the neural cell adhesion molecule (NCAM) in axon guidance [102,[109][110][111][112][113], the synapse-associated protein of 25 kDa (SNAP25), NMDA receptor type I (NMDAR1), BK and Ca ++ channels and neurexin in synaptic function [8,96,108,[114][115][116][117][118][119][120][121][122][123], the intracellular plasma-membrane calcium-pump isoforms 2 and 4 (PMCA2 and 4) and inositol triphosphate receptor type 1 (IP3R1) in Ca ++ homeostasis [124][125][126][127][128][129][130][131][132], the caspase ICH-1 in neuronal survival/death [98,101,133], and the splicing factors Tra2 beta1 and Ania-6 in pre-mRNA splicing [99,106,[134][135][136] (Table 1).…”

Section: Alternative Exons Regulated By Ca ++ Signalsmentioning

confidence: 99%

“…Inclusion of these alternative exons regulates the subcellular localization of proteins or their functions [25,26,119,120,[127][128][129]123,125,134,[137][138][139][140][141], ranging from subtle changes such as current kinetics of ion channels to on or off switches in the sensitivity to protein kinases or hormones [26,114,139,[142][143][144] (Table 1). These observations suggest that the regulation of alternative splicing by Ca ++ signals has effects on the expression of genes involved in a variety of cellular functions, from cell adhesion molecules at the synapse, ion channels in the cellular endoplasmic membrane, caspase in the cytosol as well as splicing factors inside the nucleus.…”

Section: Alternative Exons Regulated By Ca ++ Signalsmentioning

confidence: 99%

Control of alternative pre-mRNA splicing by Ca++ signals

Xie¹

2008

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Alternative pre-mRNA splicing is a common way of gene expression regulation in metazoans. The selective use of specific exons can be modulated in response to various manipulations that alter Ca ++ signals, particularly in neurons. A number of splicing factors have also been found to be controlled by Ca ++ signals. Moreover, pre-mRNA elements have been identified that are essential and sufficient to mediate Ca ++ -regulated splicing, providing model systems for dissecting the involved molecular components. In neurons, this regulation likely contributes to the fine-tuning of neuronal properties.

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“…PMCA1b prevails instead in basolateral membranes. Recent work has shown that the truncated isoform in the stereocilia of OHCs is also spliced at site A and is thus the w/a variant (31). It is plausible to assume that the choice of this unusual variant of the PMCA (32) was dictated by the special Ca 2ϩ homeostasis demands of the ambient in which the pump must operate.…”

mentioning

confidence: 99%

A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness

Ficarella

Leva²,

Bortolozzi

et al. 2007

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

113

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Ca 2؉ enters the stereocilia of hair cells through mechanoelectrical transduction channels opened by the deflection of the hair bundle and is exported back to endolymph by an unusual splicing isoform (w/a) of plasma-membrane calcium-pump isoform 2 (PMCA2). Ablation or missense mutations of the pump cause deafness, as described for the G283S mutation in the deafwaddler (dfw) mouse. A deafness-inducing missense mutation of PMCA2 (G293S) has been identified in a human family. The family also was screened for mutations in cadherin 23, which accentuated hearing loss in a previously described human family with a PMCA2 mutation. A T1999S substitution was detected in the cadherin 23 gene of the healthy father and affected son but not in that of the unaffected mother, who presented instead the PMCA2 mutation. The w/a isoform was overexpressed in CHO cells. At variance with the other PMCA2 isoforms, it became activated only marginally when exposed to a Ca 2؉ pulse. The G293S and G283S mutations delayed the dissipation of Ca 2؉ transients induced in CHO cells by InsP3. In organotypic cultures, Ca 2؉ imaging of vestibular hair cells showed that the dissipation of stereociliary Ca 2؉ transients induced by Ca 2؉ uncaging was compromised in the dfw and PMCA2 knockout mice, as was the sensitivity of the mechanoelectrical transduction channels to hair bundle displacement in cochlear hair cells.hereditary hearing loss ͉ mutations ͉ calcium homeostasis ͉ calcium transport T he receptive organelle of sensory hair cells in the mammalian cochlea, the stereocilia bundle, protrudes from the cell's apical surface. Inner hair cells transduce mechanical vibrations into electrical signals that are eventually transmitted to the brain to be transformed into hearing signals (1), whereas outer hair cells (OHCs) (2) amplify the vibrations of the basilar membrane (3). Mechanical stimuli that are detected as excitatory deflect a hair bundle, thus increasing tension in the tip link, a filament stretched between the tops of stereocilia. This tension is conveyed to mechanosensitive transduction (MET) channels that open to allow ions into the cell (4). The apical surface of hair cells is bathed in endolymph, which is rich in K ϩ but low in Na ϩ and Ca 2ϩ (5). K ϩ carries most the transduction current, but MET channels are Ca 2ϩ selective, i.e., Ca 2ϩ influx is significant even at the low Ca 2ϩ levels of the endolymph, which are much lower than those of other extracellular fluids (6-10): 20-23 M in the rodent cochlea (11, 12), 200-250 M in the vestibular system, possibly because of the presence there of calcium carbonate crystals (13,14). Approximately 10% of the MET current may actually be carried by Ca 2ϩ ions (15). Ca 2ϩ entering through MET channels is rapidly sequestered by buffers in the stereocilia (16,17) and is shuttled back to endolymph by the plasma membrane Ca 2ϩ pump (PMCA) (18,19), which is very concentrated in the stereocilia membrane (Ϸ2,000 per squared micrometer) (15, 19-21). The PMCA is assumed to increase Ca 2ϩ in the immediate pro...

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Splice-Site A Choice Targets Plasma-Membrane Ca2+-ATPase Isoform 2 to Hair Bundles

Cited by 68 publications

References 58 publications

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs

Control of alternative pre-mRNA splicing by Ca++ signals

A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness

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