Centre for Craniofacial and Regenerative Biology, Floor 27 Tower Wing, Guy's Hospital, King's College London, London, SE1 9RT, UK.
Leukaemia and Stem Cell Biology Group, School of Cancer and Pharmaceutical Sciences, King's College London, London, SE5 9NU, UK.
Commun Biol. 2021 Nov 3;4(1):1260. doi: 10.1038/s42003-021-02788-6.
Neurons and sensory cells are particularly vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission. The mechanisms that protect them from stress-induced death and degeneration remain elusive. Here we show that embryonic deletion of the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons or hair cells leads to sensorineural hearing loss due to postnatal degeneration of both cell types. Mechanistically, we demonstrate that CHD7 controls the expression of major stress pathway components. In its absence, hair cells are hypersensitive, dying rapidly after brief exposure to stress inducers, suggesting that sound at the onset of hearing triggers their degeneration. In humans, CHD7 haploinsufficiency causes CHARGE syndrome, a disorder affecting multiple organs including the ear. Our findings suggest that CHD7 mutations cause developmentally silent phenotypes that predispose cells to postnatal degeneration due to a failure of protective mechanisms.
神经元和感觉细胞由于在刺激感知和传递过程中需要大量氧气，因此特别容易受到氧化应激的影响。然而，保护它们免受应激诱导的死亡和退化的机制仍难以捉摸。在这里，我们表明，在听觉神经元或毛细胞中胚胎期删除染色质解旋酶 DNA 结合蛋白 7（CHD7）会导致感觉神经性听力损失，这是由于两种细胞类型的后天性退化引起的。从机制上讲，我们证明 CHD7 控制着主要应激途径成分的表达。在 CHD7 缺失的情况下，毛细胞变得非常敏感，在短暂暴露于应激诱导剂后迅速死亡，这表明听力开始时的声音会引发它们的退化。在人类中，CHD7 杂合性不足会导致 CHARGE 综合征，这是一种影响包括耳朵在内的多个器官的疾病。我们的研究结果表明，CHD7 突变导致发育性沉默表型，由于保护机制的失败，使细胞易发生后天性退化。
