Progressive Deafness and Altered Cochlear Innervation in Knock-Out Mice Lacking Prosaposin

Akil, Omar; Chang, Jolie L.; Hiel, Hakim; Kong, Jee Hyun; Yi, Eunyoung; Glowatzki, Elisabeth; Lustig, Lawrence R.

doi:10.1523/jneurosci.3746-06.2006

Cited by 27 publications

(62 citation statements)

References 56 publications

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“…This awaits differential analysis of mice with tissue-specific Ca v 1.3 deletion either in the cochlea or the brainstem. We hypothesize that the central loss has a considerable, although not exclusive impact, because other deafness-related gene mutations, which cause function loss in the cochlea, e.g., in dn/dn mice (Youssoufian et al, 2008), otoferlin otof mice (Longo-Guess et al, 2007), and prosaposin Ϫ/Ϫ mice (Akil et al, 2006), appear not to result in obvious LSO malformations. biophysical and synaptic properties analyzed, seven differed between the two phenotypes.…”

Section: Possible Causes Of the Impaired Developmentmentioning

confidence: 96%

Ca_v1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem

Hirtz

Boesen²,

Braun³

et al. 2011

J. Neurosci.

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Within the Ca v 1 family of voltage-gated calcium channels, Ca v 1.2 and Ca v 1.3 channels are the predominant subtypes in the brain. Whereas specific functions for each subtype were described in the adult brain, their role in brain development is poorly understood. Here we assess the role of Ca v 1.3 subunits in the activity-dependent development of the auditory brainstem. We used Ca v 1.3-deficient (Ca v 1.3 Ϫ/Ϫ ) mice because these mice lack cochlea-driven activity that deprives the auditory centers from peripheral input. We found a drastically reduced volume in all auditory brainstem centers (range 25-59%, total 35%), which was manifest before hearing onset. A reduction was not obvious outside the auditory system. The lateral superior olive (LSO) was strikingly malformed in Ca v 1.3 Ϫ/Ϫ mice and had fewer neurons (1/3 less). The remaining LSO neurons displayed normal dendritic trees and received functional glutamatergic input, yet they fired action potentials predominantly with a multiple pattern upon depolarization, in contrast to the single firing pattern prevalent in controls. The latter finding appears to be due to a reduction of dendrototoxin-sensitive potassium conductances, presumably mediated through the K v 1.2 subtype. Fura2 imaging provided evidence for functional Ca v 1.3 channels in the LSO of wild-type mice. Our results imply that Ca v 1.3 channels are indispensable for the development of the central auditory system. We propose that the unique LSO phenotype in Ca v 1.3 Ϫ/Ϫ mice, which hitherto was not described in other hereditary deafness models, is caused by the synergistic contribution of two factors: on-site loss of Ca v 1.3 channels in the neurons plus lack of peripheral input.

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Section: Possible Causes Of the Impaired Developmentmentioning

confidence: 96%

Ca_v1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem

Hirtz

Boesen²,

Braun³

et al. 2011

J. Neurosci.

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“…Using the cytoplasmic domain of α9 as bait, no interacting proteins were identified. Using the cytoplasmic domain of α10, Akil et al [28] identified a protein, prosaposin, which had not been described in the cochlea [28,29] . Prosaposin is a precursor of four glycoprotein activators of lysosomal hydrolases (saposin A, B, C and D).…”

Section: Importance Of the Cytoplasmic Domain In Clustering And Functmentioning

confidence: 99%

“…Prosaposin is a precursor of four glycoprotein activators of lysosomal hydrolases (saposin A, B, C and D). Systematic deletion analysis and yeast growth assays revealed that the prosaposin site for binding to α10 was localized to a 40 amino acid region in the carboxy termini, corresponding to a domain in saposin D [29] . This domain of saposin D had not been previously found to interact with other proteins.…”

Section: Importance Of the Cytoplasmic Domain In Clustering And Functmentioning

confidence: 99%

“…However, after the onset of hearing, the labeling of both of these markers was more intense and concentrated abnormally in the inner hair cell and Deiter cell regions, where cellular hyperplasia was observed. In mice lacking prosaposin, loss of outer hair cells in the apex of the cochlea was also prevalent by one month of age [29] .…”

Section: Importance Of the Cytoplasmic Domain In Clustering And Functmentioning

confidence: 99%

“…Prosaposin, or one of its mature cleaved products, saposins A-D is essential for the maintenance of innervation within the mammalian organ of Corti, and is specifically required for normal development of the efferent connections. Prosaposin ablation has specific effects on efferent functions in the auditory and vestibular epithelia, and this functional impairment may be due to lack of direct interaction with 10 nAChR subunit, as indicated by the Y2H results [29] .…”

Section: Importance Of the Cytoplasmic Domain In Clustering And Functmentioning

confidence: 99%

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α9α10 Acetylcholine receptors: structure and functions

Vázquez

2016

Neurotransmitter

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The α9 and α10 nicotinic acetylcholine receptor (nAChR) subunits assemble as pentameric complexes with a central ligand-gated cation-selective pore. However, these subunits do not assemble with other nAChR subunits. The general topology of each subunit is similar to that of other ligand-gated, Cys-loop ion channels. Although the sequence and genomic organization of the α9 and α10 subunits determined their classification as nicotinic subunits, α9α10 nAChRs exhibit peculiar pharmacological properties that are not common to other nicotinic or muscarinic receptors. α9α10 nAChRs are expressed in diverse tissues, including auditory sensory hair cells, afferent neurons in the vestibular sensory organs, neurons of the dorsal root ganglion, skin, and bronchial epithelia. Furthermore, it has become apparent that nAChRs containing α9 and α10 subunits play essential roles in various physiological processes. For example, α9 is required for the normal development of the efferent synapses in the inner ear, and after the onset of hearing α9α10 nAChRs serve as the unique source of extracellular calcium for Ca 2+ -activated potassium channels in mature auditory hair cells. The development of drugs that selectively target α9/α10 receptors promises to be of therapeutic benefit since these receptors have distinct physiologic functions. They hold promise as pharmacological targets to treat complex auditory and vestibular pathologies, neuropathic pain, and pathologies of the skin and bronchia.

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Role of saposin C and D in auditory and vestibular function

et al. 2015

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Progressive Deafness and Altered Cochlear Innervation in Knock-Out Mice Lacking Prosaposin

Cited by 27 publications

References 56 publications

Ca_v1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem

Ca_v1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem

α9α10 Acetylcholine receptors: structure and functions

Role of saposin C and D in auditory and vestibular function

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Progressive Deafness and Altered Cochlear Innervation in Knock-Out Mice Lacking Prosaposin

Cited by 27 publications

References 56 publications

Cav1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem

Cav1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem

α9α10 Acetylcholine receptors: structure and functions

Role of saposin C and D in auditory and vestibular function

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Product

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Ca_v1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem

Ca_v1.3 Calcium Channels Are Required for Normal Development of the Auditory Brainstem