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
Neuroplastin 与钙粘蛋白 23 发生遗传相互作用，编码的亚型 Np55 足以维持耳蜗毛细胞功能和听力
DOI：
10.1101/2021.11.10.468016
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Newton S
中科院分区：
文献类型：
--
作者：
Newton S
哺乳动物的听力包括耳蜗声诱导流体波的机电转换(MET)。这一过程的关键是特殊的感觉耳蜗细胞，即内毛细胞(IHC)和外毛细胞(OHC)。虽然遗传性听力损失具有高度的异质性，但了解每个基因的要求将有助于更好地理解听力的分子基础，并为耳聋提供治疗机会。神经增殖素(NPTN)基因编码两种蛋白质亚型Np55和Np65，是听力所必需的，影响这两种亚型的纯合功能丧失突变会导致小鼠严重耳聋。在这里，我们利用几个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特异性小鼠敲除的特征显示正常的听力阈值，表明Np65在听力功能上是多余的。相反，我们发现Nptn基因敲除的小鼠显著降低了成熟的内皮腺细胞的最大MET电流和MET通道开放的概率，并且两种内皮腺细胞也都未能形成完全成熟的基底侧电流。此外，将Nptn基因敲除小鼠的听力阈值和IHC突触结构与仅在IHC和OHC中缺乏Nptn的小鼠进行比较，发现大多数听力障碍是由毛细胞功能障碍解释的，异常的传入突触只占听力损失的一小部分。最后，我们发现在成年小鼠的毛囊细胞中持续表达神经纤溶酶是质膜钙ATPase 2(PMCA2)膜定位所必需的，PMCA2对于听力功能是必不可少的。此外，Nptn单倍体不足的表型基因Atp2b2(编码PMCA2)突变，杂合的Nptn基因敲除小鼠通过与CDh23ahl等位基因的遗传相互作用而表现出听力损失。综上所述，我们的发现为哺乳动物听力对神经成形素的功能需求提供了进一步的洞察力。
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. TheNeuroplastin(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 ofNptnfor 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 thatNptn-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 ofNptn-knockout mice with those of mice that lackNptnonly 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,Nptnhaploinsufficiency phenocopiesAtp2b2(encodes PMCA2) mutations, with heterozygousNptn-knockout mice exhibiting hearing loss through genetic interaction with theCdh23ahlallele. Together, our findings provide further insight to the functional requirement ofNeuroplastinfor mammalian hearing.
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影响因子：
5.3
作者：
Dumont, RA;Lins, U;Gillespie, PG
通讯作者：
Gillespie, PG
影响因子：
4.8
作者：
Herrera-Molina, Rodrigo;Sarto-Jackson, Isabella;Montag, Dirk
通讯作者：
Montag, Dirk
影响因子：
4.6
作者：
Herrera-Molina R;Mlinac-Jerkovic K;Ilic K;Stöber F;Vemula SK;Sandoval M;Milosevic NJ;Simic G;Smalla KH;Goldschmidt J;Bognar SK;Montag D
通讯作者：
Montag D
影响因子：
16.2
作者：
Schmidt, Nadine;Kollewe, Astrid;Schulte, Uwe
通讯作者：
Schulte, Uwe
神经塑料和质膜Ca（2+）ATPase的复合物控制T细胞激活。
影响因子：
4.6
作者：
Korthals M;Langnaese K;Smalla KH;Kähne T;Herrera-Molina R;Handschuh J;Lehmann AC;Mamula D;Naumann M;Seidenbecher C;Zuschratter W;Tedford K;Gundelfinger ED;Montag D;Fischer KD;Thomas U
通讯作者：
Thomas U