Neuroplastin genetically interacts with Cadherin 23 and the encoded isoform Np55 is sufficient for cochlear hair cell function and hearing.
Neuroplastin genetically interacts with Cadherin 23 and the encoded isoform Np55 is sufficient for cochlear hair cell function and hearing.
复制标题
神经塑料与钙粘蛋白23的遗传相互作用，编码的同工型NP55足以足以完成耳蜗功能和听力。
DOI：
10.1371/journal.pgen.1009937
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发表时间：
2022-01
期刊：
影响因子：
4.5
通讯作者：
Bowl MR
中科院分区：
文献类型：
--
作者：
Newton S;Kong F;Carlton AJ;Aguilar C;Parker A;Codner GF;Teboul L;Wells S;Brown SDM;Marcotti W;Bowl MR
哺乳动物的听觉涉及耳蜗内声诱导的流体波的机电转导（MET）。在这个过程中至关重要的是专门的感觉耳蜗细胞，内耳毛细胞（IHCs）和外耳毛细胞（OHCs）。虽然遗传性听力损失是高度异质性的，但了解每个基因的需求将有助于更好地了解听力的分子基础，并为耳聋的治疗提供机会。神经活素（Nptn）基因编码两种蛋白质异构体Np55和Np65，是听力所必需的，影响这两种异构体的纯合子功能丧失突变导致小鼠重度耳聋。在这里，我们利用几种不同的小鼠模型来详细说明Nptn对听力的空间、时间和功能要求。虽然我们证明Np55和Np65都存在于耳蜗细胞中，但对Np65特异性敲除小鼠的特征分析显示，听力阈值正常，表明Np65在听力功能上是冗余的。相反，我们发现nptn敲除小鼠在成熟OHCs中显著降低了最大MET电流和MET通道打开概率，OHCs和ihc也无法形成完全成熟的基底外侧电流。此外，将Nptn敲除小鼠的听力阈值和IHC突触结构与仅在IHC和OHCs中缺乏Nptn的小鼠的听力阈值和IHC突触结构进行比较，发现大部分听力缺陷是由毛细胞功能障碍解释的，传入突触异常仅占听力损失的一小部分。最后，我们发现神经活素在成年小鼠OHCs中的持续表达是质膜Ca2+ atp酶2 （PMCA2）的膜定位所必需的，这对听力功能至关重要。此外，Nptn单倍不足表型导致Atp2b2（编码PMCA2）突变，杂合Nptn敲除小鼠通过与Cdh23ahl等位基因的遗传相互作用表现出听力损失。总之，我们的研究结果进一步揭示了神经生长素对哺乳动物听力的功能需求。由耳蜗或听神经的感觉细胞问题引起的感觉神经性听力损失是最常见的听力损失类型。神经活素的突变已经与小鼠的耳聋有关。我们使用突变小鼠模型来研究神经活素在耳蜗中的表达位置及其功能。当小鼠不表达神经活蛋白的功能拷贝时，它们的主要感觉突触就会受到破坏。我们表明，虽然突触破坏有助于听力功能的丧失，但它不是主要原因。相反，需要神经活素的持续表达来维持质膜Ca2+ atp酶2通道的定位，这有助于调节钙的流动。我们还表明，两种类型的神经活素蛋白（同种异构体）都在耳蜗内表达，尽管这些同种异构体中只有一种需要表达才能正常听力。最后，我们还证明，当与钙粘蛋白23 （Cdh23ahl）基因中的常见突变结合时，由神经活蛋白缺失引起的听力损失会变得更糟。重要的是，虽然到目前为止还没有关于神经活蛋白突变直接导致患者听力损失的报道，但该基因的变异可能与人类耳聋以及其他遗传病变有关。
Mammalian hearing involves the mechanoelectrical transduction (MET) of sound-induced fluid waves in the cochlea. Essential to this process are the specialised sensory cochlear cells, the inner (IHCs) and outer hair cells (OHCs). While genetic hearing loss is highly heterogeneous, understanding the requirement of each gene will lead to a better understanding of the molecular basis of hearing and also to therapeutic opportunities for deafness. The Neuroplastin (Nptn) gene, which encodes two protein isoforms Np55 and Np65, is required for hearing, and homozygous loss-of-function mutations that affect both isoforms lead to profound deafness in mice. Here we have utilised several distinct mouse models to elaborate upon the spatial, temporal, and functional requirement of Nptn for hearing. While we demonstrate that both Np55 and Np65 are present in cochlear cells, characterisation of a Np65-specific mouse knockout shows normal hearing thresholds indicating that Np65 is functionally redundant for hearing. In contrast, we find that Nptn-knockout mice have significantly reduced maximal MET currents and MET channel open probabilities in mature OHCs, with both OHCs and IHCs also failing to develop fully mature basolateral currents. Furthermore, comparing the hearing thresholds and IHC synapse structure of Nptn-knockout mice with those of mice that lack Nptn only in IHCs and OHCs shows that the majority of the auditory deficit is explained by hair cell dysfunction, with abnormal afferent synapses contributing only a small proportion of the hearing loss. Finally, we show that continued expression of Neuroplastin in OHCs of adult mice is required for membrane localisation of Plasma Membrane Ca2+ ATPase 2 (PMCA2), which is essential for hearing function. Moreover, Nptn haploinsufficiency phenocopies Atp2b2 (encodes PMCA2) mutations, with heterozygous Nptn-knockout mice exhibiting hearing loss through genetic interaction with the Cdh23ahl allele. Together, our findings provide further insight to the functional requirement of Neuroplastin for mammalian hearing. Sensorineural hearing loss, caused by problems with sensory cells in the cochlea or the auditory nerve, is the most common type of hearing loss. Mutations in Neuroplastin have already been implicated in deafness in mice. We have used mutant mouse models to investigate where Neuroplastin is expressed in the cochlea and its function. When mice do not express a functioning copy of Neuroplastin they have disruptions to the primary sensory synapse. We show that although synaptic disruption contributes to the loss of hearing function it is not the primary cause. Instead, continued expression of Neuroplastin is needed to maintain the localisation of Plasma Membrane Ca2+ ATPase 2 channels which help regulate calcium flow. We have also shown that two types of Neuroplastin protein (isoforms) are both expressed within the cochlea, although only one of these isoforms needs to be expressed for normal hearing. Finally, we also demonstrate that the hearing loss caused by the absence of Neuroplastin is made worse when combined with a common mutation within a gene called Cadherin 23 (Cdh23ahl). Importantly, while to date there are no reports of NEUROPLASTIN mutations directly causing hearing loss in patients, variants in this gene may be involved in human deafness in combination with other genetic lesions.
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影响因子：
1.5
作者：
Fang, Jie;Zhang, Wen-Cheng;Yamashita, Tetsuji;Gao, Jiangang;Zhu, Min-Sheng;Zuo, Jian
通讯作者：
Zuo, Jian
DOI：
10.1113/jp279795
发表时间：
2020-09
期刊：
The Journal of physiology
影响因子：
--
作者：
Jeng JY;Johnson SL;Carlton AJ;De Tomasi L;Goodyear RJ;De Faveri F;Furness DN;Wells S;Brown SDM;Holley MC;Richardson GP;Mustapha M;Bowl MR;Marcotti W
通讯作者：
Marcotti W
影响因子：
16.6
作者：
Bowl MR;Simon MM;Ingham NJ;Greenaway S;Santos L;Cater H;Taylor S;Mason J;Kurbatova N;Pearson S;Bower LR;Clary DA;Meziane H;Reilly P;Minowa O;Kelsey L;International Mouse Phenotyping Consortium;Tocchini-Valentini GP;Gao X;Bradley A;Skarnes WC;Moore M;Beaudet AL;Justice MJ;Seavitt J;Dickinson ME;Wurst W;de Angelis MH;Herault Y;Wakana S;Nutter LMJ;Flenniken AM;McKerlie C;Murray SA;Svenson KL;Braun RE;West DB;Lloyd KCK;Adams DJ;White J;Karp N;Flicek P;Smedley D;Meehan TF;Parkinson HE;Teboul LM;Wells S;Steel KP;Mallon AM;Brown SDM
通讯作者：
Brown SDM
影响因子：
16.6
作者：
Corns LF;Johnson SL;Roberts T;Ranatunga KM;Hendry A;Ceriani F;Safieddine S;Steel KP;Forge A;Petit C;Furness DN;Kros CJ;Marcotti W
通讯作者：
Marcotti W
影响因子：
11.1
作者：
Dunbar, Lucy A.;Patni, Pranav;Bowl, Michael R.
通讯作者：
Bowl, Michael R.