Chromatin remodeler CHD7 is critical for cochlear morphogenesis and neurosensory patterning.
Chromatin remodeler CHD7 is critical for cochlear morphogenesis and neurosensory patterning.
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DOI：
10.1016/j.ydbio.2021.05.009
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发表时间：
2021-09
影响因子：
2.7
通讯作者：
Martin DM
中科院分区：
文献类型：
--
作者：
Balendran V;Skidmore JM;Ritter KE;Gao J;Cimerman J;Beyer LA;Hurd EA;Raphael Y;Martin DM
染色质重塑蛋白对基因转录的表观遗传调控最近成为内耳发育的一个重要因素。CHD 7（编码染色体结构域解旋酶DNA结合蛋白7的基因）中的致病性变体导致CHARGE综合征，该综合征在发育中的耳朵中表现为畸形。Chd 7在发育中的小鼠耳囊和成熟的听觉上皮中广泛表达，但Chd 7缺失在耳蜗中的致病作用尚不清楚。在这里，我们的特点是耳蜗上皮细胞表型缺失Chd 7在整个耳囊（使用Foxg 1Cre/+和Pax 2Cre），在耳间充质（使用TCre），在毛细胞（使用Atoh 1Cre），在发展中的神经母细胞（使用NgnCre），或在螺旋神经节神经元（使用ShhCre/+）的小鼠。Chd 7的全耳缺失导致耳蜗缩短，伴有异常投射和轴突成环，顶端转向处的紊乱的编外毛细胞和中部区域的上皮变窄且缺少毛细胞。耳间充质中Chd 7的缺失对整体耳蜗形态没有影响。毛细胞中Chd 7的缺失并没有破坏它们的形成或听觉上皮的组织。同样，螺旋神经节神经元中Chd 7的缺失对轴突投射没有影响。与此相反，Chd 7在发育中的神经母细胞中的缺失导致较小的螺旋神经节和紊乱的耳蜗神经突。总之，这些观察结果揭示了剂量，组织和时间敏感的细胞自主作用的Chd 7在耳蜗伸长和耳蜗神经元组织，与最小的功能Chd 7在毛细胞。这些研究为Chd 7在听觉神经元发育中的作用提供了新的信息。
Epigenetic regulation of gene transcription by chromatin remodeling proteins has recently emerged as an important contributing factor in inner ear development. Pathogenic variants in CHD7, the gene encoding Chromodomain Helicase DNA binding protein 7, cause CHARGE syndrome, which presents with malformations in the developing ear. Chd7 is broadly expressed in the developing mouse otocyst and mature auditory epithelium, yet the pathogenic effects of Chd7 loss in the cochlea are not well understood. Here we characterized cochlear epithelial phenotypes in mice with deletion of Chd7 throughout the otocyst (using Foxg1Cre/+ and Pax2Cre), in the otic mesenchyme (using TCre), in hair cells (using Atoh1Cre), in developing neuroblasts (using NgnCre), or in spiral ganglion neurons (using ShhCre/+). Pan-otic deletion of Chd7 resulted in shortened cochleae with aberrant projections and axonal looping, disorganized, supernumerary hair cells at the apical turn and a narrowed epithelium with missing hair cells in the middle region. Deletion of Chd7 in the otic mesenchyme had no effect on overall cochlear morphology. Loss of Chd7 in hair cells did not disrupt their formation or organization of the auditory epithelium. Similarly, absence of Chd7 in spiral ganglion neurons had no effect on axonal projections. In contrast, deletion of Chd7 in developing neuroblasts led to smaller spiral ganglia and disorganized cochlear neurites. Together, these observations reveal dosage-, tissue-, and time-sensitive cell autonomous roles for Chd7 in cochlear elongation and cochlear neuron organization, with minimal functions for Chd7 in hair cells. These studies provide novel information about roles for Chd7 in development of auditory neurons.
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影响因子：
3.5
作者：
Bosman, EA;Penn, AC;Steel, KP
通讯作者：
Steel, KP
影响因子：
2.1
作者：
Green, Glenn E.;Huq, Farhan S.;Martin, Donna M.
通讯作者：
Martin, Donna M.
DOI：
10.1073/pnas.1222341110
发表时间：
2013-08-20
影响因子：
11.1
作者：
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通讯作者：
Wu, Doris K.
影响因子：
2.5
作者：
Adams, Meredith E.;Hurd, Elizabeth A.;Martin, Donna M.
通讯作者：
Martin, Donna M.
影响因子：
4.6
作者：
Kiernan, AE;Cordes, R;Gridley, T
通讯作者：
Gridley, T