Atoh1 expression and function during auditory hair cell regeneration in post-hatch chickens
Atoh1 expression and function during auditory hair cell regeneration in post-hatch chickens
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DOI：
10.1016/j.heares.2012.04.008
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发表时间：
2012-07-01
期刊：
影响因子：
2.8
通讯作者：
Stone, Jennifer S.
中科院分区：
文献类型：
--
作者：
Lewis, Rebecca M.;Hume, Clifford R.;Stone, Jennifer S.
人类毛细胞的丧失会导致不可逆转的听力缺陷，因为听觉毛细胞不会被替换。相比之下，成熟鸟类的听觉上皮细胞在受到非感觉支持细胞损伤后会再生，这些支持细胞通过有丝分裂和/或非有丝分裂机制转分化为毛细胞。人们对控制这些过程的因素知之甚少。基本的螺旋-环-螺旋转录因子 ATOH1 对于发育性毛细胞分化来说是必要且充分的，但尚不清楚它是否在毛细胞再生的有丝分裂和非有丝分裂途径中发挥相同的作用。我们检查了鸡毛细胞再生过程中 Atoh1 的表达和功能。施用耳毒素后不久，Atoh1 转录物在受损听觉上皮的许多支持细胞中增加，随后仅限于分化毛细胞。使用 Atoh1 增强子报道基因进行的体外命运图谱表明，在损伤后自发上调 Atoh1 增强子活性的支持细胞中，只有 56% 获得了毛细胞命运。使用γ分泌酶拮抗剂抑制Notch信号传导会刺激Atoh1报告活性的增加，并诱导更高比例的具有Atoh1活性的支持细胞（73%）分化为毛细胞。 Atoh1 在支持细胞中的强制过度表达触发了 66% 的支持细胞获得毛细胞命运，并使它们进入细胞周期的可能性几乎增加了三倍。这些发现表明 Atoh1 在损伤后在支持细胞中广泛上调，但很大一部分 Atoh1 激活的支持细胞未能获得毛细胞特征，部分原因是γ分泌酶依赖性活性。 (C) 2012 Elsevier B.V. 保留所有权利。
Loss of hair cells in humans leads to irreversible hearing deficits, since auditory hair cells are not replaced. In contrast, hair cells are regenerated in the auditory epithelium of mature birds after damage by non-sensory supporting cells that transdifferentiate into hair cells by mitotic and/or non-mitotic mechanisms. Factors controlling these processes are poorly understood. The basic helix-loop-helix transcription factor ATOH1, is both necessary and sufficient for developmental hair cell differentiation, but it is unclear if it plays the same role in the mitotic and non-mitotic pathways in hair cell regeneration. We examined Atoh1 expression and function during hair cell regeneration in chickens. Atoh1 transcripts were increased in many supporting cells in the damaged auditory epithelium shortly after ototoxin administration and later became restricted to differentiating hair cells. Fate-mapping in vitro using an Atoh1 enhancer reporter demonstrated that only 56% of the supporting cells that spontaneously upregulate Atoh1 enhancer activity after damage acquired the hair cell fate. Inhibition of notch signaling using a gamma secretase antagonist stimulated an increase in Atoh1 reporter activity and induced a higher proportion of supporting cells with Atoh1 activity (73%) to differentiate as hair cells. Forced overexpression of Atoh1 in supporting cells triggered 66% of them to acquire the hair cell fate and nearly tripled their likelihood of cell cycle entry. These findings demonstrate that Atoh1 is broadly upregulated in supporting cells after damage, but a substantial proportion of supporting cells with Atoh1 activation fails to acquire hair cell features, in part due to gamma secretase-dependent activities. (C) 2012 Elsevier B.V. All rights reserved.