Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, USA.
Section On Sensory Cell Regeneration and Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, 20892, USA.
Sci Rep. 2023 Aug 3;13(1):12573. doi: 10.1038/s41598-023-39707-0.
It has previously been shown that the zinc-finger transcription factor Gata3 has dynamic expression within the inner ear throughout embryonic development and is essential for cochlear neurosensory development. However, the temporal window for which Gata3 is required for proper formation of the cochlear neurosensory epithelia remains unclear. To investigate the role of Gata3 in cochlear neurosensory development in the late prosensory stages, we used the Sox2-cre mouse line to target and conditionally delete Gata3 at E11.5, a timepoint before cells have fully committed to a neurosensory fate. While the inner ears of Sox2-cre: Gata3 f/f mice appear normal with no gross structural defects, the sensory cells in the organ of Corti are partially lost and disorganized in an increasing severity from base to apex. Additionally, spiral ganglion neurons display aberrant peripheral projections, including increased distances between radial bundles and disorganization upon reaching the organ of Corti. Furthermore, heterozygous Sox2-cre: Gata3 f/+ mice show a reduced aberrant phenotype in comparison to the homozygous mutant, supporting the hypothesis that Gata3 is not only required for proper formation at the later proneurosensory stage, but also that a specific expression level of Gata3 is required. Therefore, this study provides evidence that Gata3 plays a time-sensitive and dose-dependent role in the development of sensory and neuronal cells in late proneurosensory stages.
先前的研究表明，锌指转录因子 Gata3 在胚胎发育过程中在内耳中具有动态表达，对于耳蜗神经感觉发育是必不可少的。然而，Gata3 对于耳蜗神经感觉上皮正常形成所需的时间窗口尚不清楚。为了研究 Gata3 在晚期前感觉阶段耳蜗神经感觉发育中的作用，我们使用 Sox2-cre 小鼠系在 E11.5 时靶向并条件性删除 Gata3，此时细胞尚未完全决定为神经感觉命运。虽然 Sox2-cre:Gata3 f/f 小鼠的内耳外观正常，没有明显的结构缺陷，但 Corti 器中的感觉细胞部分丢失且排列紊乱，从基部到顶部逐渐加重。此外，螺旋神经节神经元显示出异常的外周投射，包括放射束之间的距离增加和到达 Corti 器时的紊乱。此外，杂合子 Sox2-cre:Gata3 f/+ 小鼠与纯合突变体相比表现出降低的异常表型，支持 Gata3 不仅在后期前神经感觉阶段对于正常形成是必需的，而且还需要特定的 Gata3 表达水平的假说。因此，本研究提供了证据表明，Gata3 在晚期前神经感觉阶段的感觉和神经元细胞发育中发挥时间敏感和剂量依赖的作用。
