ISL1 is necessary for auditory neuron development and contributes toward tonotopic organization.
ISL1 is necessary for auditory neuron development and contributes toward tonotopic organization.
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DOI：
10.1073/pnas.2207433119
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发表时间：
2022-09-13
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
关于听觉频率图的分子决定因素知之甚少。我们的数据提供了深入了解转录因子ISL 1在听觉神经元的发育和听觉地图的形成中的功能作用。在这项研究中，我们发现，选择性基因缺失的Isl1 Neurod1Cre导致听觉神经元的分子和细胞特性的改变，影响他们的迁移，寻路能力，形成外周和中央进程。这种神经元表型伴有听力障碍、大脑声音处理异常和异常听觉行为。这些发现表明，ISL 1是必不可少的调节神经元分化产生功能性听觉神经元。听觉通路的一个主要特征是频率选择性，表现为从耳蜗到皮层的音调分布图。听觉频率图的分子决定因素是未知的。在这里，我们发现转录因子ISL 1调节听觉神经元的分子和细胞特征，包括螺旋神经节的形成以及形成听觉地图的音调表达的外周和中枢过程。我们选择性地敲除Isl1在听觉神经元使用Neurod1Cre策略。在Isl 1缺失的情况下，螺旋神经节神经元迁移到中央耳蜗和更远的地方，耳蜗布线严重减少和中断。Isl1突变体的中央轴突失去了他们的地形投影和分离在耳蜗核。螺旋神经节神经元的转录组分析表明，Isl1调节神经发生，轴突发生，迁移，神经传递相关的机械，和突触通讯模式。我们发现，在耳蜗周边紊乱影响听觉的中脑和听觉行为的生理特性。令人惊讶的是，尽管有显著的听力障碍，听觉处理功能被保留，揭示了Isl1突变小鼠的中枢听觉通路的弹性和可塑性。突变小鼠具有减少的声惊吓反射、改变的前脉冲抑制和中枢代偿性神经活动过度的特征。我们的研究结果表明，ISL 1是必要的因素之一，造型听觉结构和功能的音调拓扑图。尽管如此，在Isl1缺失，随后的听觉通路的中枢可塑性不足以克服发育诱导的耳蜗外周功能障碍。
Little is known about the molecular determinants of the auditory frequency maps. Our data provide insights into the functional role of the transcription factor ISL1 in the development of auditory neurons and in the formation of the auditory map. In this study, we found that selective genetic deletion of Isl1 by Neurod1Cre resulted in altered molecular and cellular characteristics of auditory neurons, affecting their migration, pathfinding abilities, and formation of peripheral and central processes. This neuronal phenotype was accompanied by hearing impairment, abnormalities in sound processing in the brain, and aberrant auditory behavior. These findings suggest that ISL1 is essential in regulating neuronal differentiation to produce functional auditory neurons. A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.
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影响因子：
5.6
作者：
Chumak T;Tothova D;Filova I;Bures Z;Popelar J;Pavlinkova G;Syka J
通讯作者：
Syka J
影响因子：
16.2
作者：
Chambers AR;Resnik J;Yuan Y;Whitton JP;Edge AS;Liberman MC;Polley DB
通讯作者：
Polley DB
DOI：
10.1073/pnas.1222341110
发表时间：
2013-08-20
影响因子：
11.1
作者：
Bok, Jinwoong;Zenczak, Colleen;Wu, Doris K.
通讯作者：
Wu, Doris K.
影响因子：
16.6
作者：
Defourny, Jean;Poirrier, Anne-Lise;Malgrange, Brigitte
通讯作者：
Malgrange, Brigitte
DOI：
10.1016/s0736-5748(98)00043-4
发表时间：
1998-10-01
影响因子：
1.8
作者：
Fritzsch, B;Barbacid, M;Silos-Santiago, I
通讯作者：
Silos-Santiago, I