Functional Development of Hair Cells

描述（由申请人提供）：跨膜耳蜗表达基因1 （TMC1）突变是显性进行性听力损失（DFNA36）和隐性非综合征感音神经性听力损失耳聋（DFNB7/B11）的基础（Kurima et al., 2002）。同样，Tmc1的半显性和隐性等位基因导致Beethoven （Bth）和Deafness （dn）突变小鼠的听力损失（Vreugde et al.,2002; Kurima et al.,2002）。Tmc1是Tmc基因家族的一员，该家族在哺乳动物中还包括其他7个类似基因（Keresztes et al., 2003）。Tmc1和Tmc2在内耳毛细胞中表达。我们最近证明缺乏Tmc1和Tmc2的小鼠会失聪并遭受严重的前庭功能障碍。有趣的是，对Corti器官发育过程中Tmc1和Tmc2 mRNA表达的分析揭示了一种异位表达模式和从Tmc2到Tmc1的发育转换（Kawashima, G¿l¿oc et al. 2011）。Tmc2 mRNA表达的上升与毛细胞转导的发育获得一致。对缺乏Tmc1或Tmc2小鼠耳蜗外毛细胞的传导电流分析显示，在出生后第一周内，耳蜗外毛细胞的传导电流几乎正常。另一方面，缺乏Tmc1和Tmc2的双敲除小鼠的毛细胞在发育过程中的任何时间点或沿Corti器官的任何区域都对机械刺激没有反应，尽管存在正常的毛束形态。基于这些观察结果，我们假设Tmc1和Tmc2具有冗余功能，并且Tmc1或Tmc2的表达是毛细胞机械转导所必需的。由于Tmc2在出生后第一周内的表达是短暂的，因此在出生后第一周结束时向Tmc1的发育转换可以解释小鼠和人类中与Tmc1突变相关的耳聋表型。为了探索Tmc1和Tmc2表达的时间限制、表达的发育开关及其功能冗余，我们将建立几种具有条件删除、条件表达和诱导表达Tmc1和Tmc2的新型小鼠模型，并检测其机械传导和听觉功能特性的变化。

DESCRIPTION (provided by applicant): Mutations in the transmembrane cochlear expressed gene 1 (TMC1) underlies dominant progressive hearing loss (DFNA36) and recessive nonsyndromic sensorineural hearing loss deafness (DFNB7/B11) (Kurima et al., 2002). Similarly, semidominant and recessive alleles of Tmc1 cause hearing loss in Beethoven (Bth) and Deafness (dn) mutant mice (Vreugde et al.,2002; Kurima et al., 2002). Tmc1 is a member of the Tmc gene family that includes seven other paralogs in mammals (Keresztes et al., 2003). Tmc1 and Tmc2 are expressed in hair cells of the inner ear. We have recently demonstrated that mice that lack Tmc1 and Tmc2 are deaf and suffer profound vestibular dysfunction. Interestingly, analysis of Tmc1 and Tmc2 mRNA expression during organ of Corti development revealed a tonotopic expression pattern and a developmental switch from Tmc2 to Tmc1 (Kawashima, G¿l¿oc et al. 2011). The rise of Tmc2 mRNA expression coincided with the developmental acquisition of hair cell transduction. Analysis of transduction currents in cochlear outer hair cells of mice lacking Tmc1 or Tmc2 revealed nearly normal responses during the first postnatal week. On the other hand, hair cells from double knockout mice that lacked Tmc1 and Tmc2 did not respond to mechanical stimulation at any time point during development or in any region along the organ of Corti despite the presence of normal hair bundle morphology. Based on these observations we hypothesize that Tmc1 and Tmc2 have redundant functions and that expression of either Tmc1 or Tmc2 is required for hair cell mechanotransduction. Since Tmc2 expression is transient during the first postnatal week, the developmental switch to Tmc1 at the end of the first postnatal week could explain the deafness phenotype associated with mutations in Tmc1 in mice and humans. To explore the temporal constraints of Tmc1 and Tmc2 expression, the developmental switch in expression and their functional redundancy, we will generate several novel mouse models with conditional deletion, conditional expression and inducible expression of Tmc1 and Tmc2 and assay for changes in the properties of mechanotranduction and auditory function.