PDF(Pubmed)
Abstract：
The inner ear houses two sensory modalities: the hearing organ, located in the cochlea, and the balance organs, located throughout the vestibular regions of the ear. Both hearing and vestibular sensory regions are composed of similar cell types, including hair cells and associated supporting cells. Recently, we showed that Notch1 is required for maintaining supporting cell survival postnatally during cochlear maturation. However, it is not known whether Notch1 plays a similar role in the balance organs of the inner ear. To characterize the role of Notch during vestibular maturation, we conditionally deleted Notch1 from Sox2-expressing cells of the vestibular organs in the mouse at P0/P1. Histological analyses showed a dramatic loss of supporting cells accompanied by an increase in type II hair cells without cell death, indicating the supporting cells are converting to hair cells in the maturing vestibular regions. Analysis of 6-week old animals indicate that the converted hair cells survive, despite the reduction of supporting cells. Interestingly, measurements of vestibular sensory evoked potentials (VsEPs), known to be generated in the striolar regions of the vestibular afferents in the maculae, failed to show a response, indicating that NOTCH1 expression is critical for striolar function postnatally. Consistent with this, we find that the specialized type I hair cells in the striola fail to develop the complex calyces typical of these cells. These defects are likely due to the reduction in supporting cells, which have previously been shown to express factors critical for the striolar region. Similar to other mutants that lack proper striolar development, Notch1 mutants do not exhibit typical vestibular behaviors such as circling and head shaking, but do show difficulties in some vestibular tests, including the balance beam and forced swim test. These results indicate that, unlike the hearing organ in which the supporting cells undergo cell death, supporting cells in the balance regions retain the ability to convert to hair cells during maturation, which survive into adulthood despite the reduction in supporting cells.
摘要：
内耳有两种感觉模式：听觉器官，位于耳蜗，和平衡器官，位于整个耳朵的前庭区域。听觉和前庭感觉区都由相似的细胞类型组成，包括毛细胞和相关的支持细胞。最近,我们表明Notch1是在耳蜗成熟过程中维持出生后支持细胞存活所必需的。然而,目前尚不清楚Notch1是否在内耳的平衡器官中起着类似的作用。为了表征Notch在前庭成熟过程中的作用，我们在P0/P1时从小鼠前庭器官的Sox2表达细胞中有条件地删除了Notch1。组织学分析显示支持细胞的急剧损失，伴随着II型毛细胞的增加而没有细胞死亡，表明支持细胞在成熟的前庭区转化为毛细胞。对6周龄动物的分析表明，转化的毛细胞存活，尽管支持细胞减少。有趣的是,前庭感觉诱发电位（VsEP）的测量，已知在黄斑前庭传入的纹状体区域产生，未能显示响应，表明NOTCH1的表达对出生后的纹状体功能至关重要。与此一致，我们发现纹状体中的特殊I型毛细胞无法发育出这些细胞典型的复杂花簇。这些缺陷可能是由于支持细胞的减少，先前已显示表达对纹状体区域至关重要的因子。类似于其他缺乏适当纹状体发育的突变体，Notch1突变体不表现出典型的前庭行为，如盘旋和摇头，但是在一些前庭测试中确实显示出困难，包括平衡木和强制游泳测试。这些结果表明,与支持细胞经历细胞死亡的听觉器官不同，平衡区域的支持细胞在成熟过程中保持转化为毛细胞的能力，尽管支持细胞减少，它们仍存活到成年。
■Notch信号调节内耳发育过程中毛细胞和支持细胞之间的细胞命运选择。然而,一旦确定了细胞命运，关于Notch在哺乳动物前庭感觉器官中的作用知之甚少。这里,我们研究了Notch1在成熟平衡器官中的作用。我们表明，Notch1的缺失导致3个月大的前庭生理和行为功能障碍。组织学分析显示，支持细胞正在转化为胞囊中的II型毛细胞，尽管失去了支持细胞，毛细胞存活到成年。此外,对于产生VsEP反应重要的纹状体I型毛细胞的数量减少，并且没有适当地神经支配。这些结果表明，Notch在出生后继续维持前庭器官的支持细胞身份，这在毛细胞再生策略中可能很重要。
■Notch信号调节内耳发育过程中毛细胞和支持细胞之间的细胞命运选择。然而,一旦确定了细胞命运，关于Notch在哺乳动物前庭感觉器官中的作用知之甚少。这里,我们研究了Notch1在成熟平衡器官中的作用。我们表明，Notch1的缺失导致3个月大的前庭生理和行为功能障碍。组织学分析显示，支持细胞正在转化为胞囊中的II型毛细胞，尽管失去了支持细胞，毛细胞存活到成年。此外,对于产生VsEP反应重要的纹状体I型毛细胞的数量减少，并且没有适当地神经支配。这些结果表明，Notch在出生后继续维持前庭器官的支持细胞身份，这在毛细胞再生策略中可能很重要。
