Department of Biomedical Science, University of Sheffield, Sheffield, UK.
Department of Otolaryngology, Tübingen Hearing Research Center, Section of Physiological Acoustics and Communication, University of Tübingen, 72076, Tübingen, Germany.
J Physiol. 2019 Jul;597(13):3389-3406. doi: 10.1113/JP277997. Epub 2019 May 28.
The physiological maturation of auditory hair cells and their innervation requires precise temporal and spatial control of cell differentiation. The transcription factor gata3 is essential for the earliest stages of auditory system development and for survival and synaptogenesis in auditory sensory afferent neurons. We show that during postnatal development in the mouse inner ear gata3 is required for the biophysical maturation, growth and innervation of inner hair cells; in contrast, it is required only for the survival of outer hair cells. Loss of gata3 in inner hair cells causes progressive hearing loss and accounts for at least some of the deafness associated with the human hypoparathyroidism, deafness and renal anomaly (HDR) syndrome. The results show that gata3 is critical for later stages of mammalian auditory system development where it plays distinct, complementary roles in the coordinated maturation of sensory hair cells and their innervation.
The zinc finger transcription factor gata3 regulates inner ear development from the formation of the embryonic otic placode. Throughout development, gata3 is expressed dynamically in all the major cochlear cell types. Its role in afferent formation is well established but its possible involvement in hair cell maturation remains unknown. Here, we find that in heterozygous gata3 null mice (gata3 ) outer hair cells (OHCs) differentiate normally but their numbers are significantly lower. In contrast, inner hair cells (IHCs) survive normally but they fail to acquire adult basolateral membrane currents, retain pre-hearing current and efferent innervation profiles and have fewer ribbon synapses. Targeted deletion of gata3 driven by otoferlin-cre recombinase (gata3 otof-cre ) in IHCs does not affect OHCs or the number of IHC afferent synapses but it leads to a failure in IHC maturation comparable to that observed in gata3 mice. Auditory brainstem responses in gata3 otof-cre mice reveal progressive hearing loss that becomes profound by 6-7 months, whilst distortion product otoacoustic emissions are no different to control animals up to this age. Our results, alongside existing data, indicate that gata3 has specific, complementary functions in different cell types during inner ear development and that its continued expression in the sensory epithelium orchestrates critical aspects of physiological development and neural connectivity. Furthermore, our work indicates that hearing loss in human hypoparathyroidism, deafness and renal anomaly (HDR) syndrome arises from functional deficits in IHCs as well as loss of function from OHCs and both afferent and efferent neurons.
听觉毛细胞及其神经支配的生理成熟需要细胞分化的精确时空控制。转录因子 Gata3 对于听觉系统发育的最早阶段以及听觉感觉传入神经元的存活和突触形成至关重要。我们表明，在小鼠内耳的出生后发育过程中，Gata3 对于内毛细胞的生物物理成熟、生长和神经支配是必需的；相比之下，它仅对内毛细胞的存活是必需的。Gata3 在毛细胞中的缺失会导致进行性听力损失，并解释了与人类甲状旁腺功能减退症、耳聋和肾脏异常（HDR）综合征相关的至少部分耳聋。结果表明，Gata3 对于哺乳动物听觉系统发育的后期阶段至关重要，在该阶段，它在感觉毛细胞及其神经支配的协调成熟中发挥着独特的、互补的作用。
锌指转录因子 Gata3 从胚胎耳板的形成开始调节内耳发育。在整个发育过程中，Gata3 在内耳的所有主要细胞类型中都动态表达。其在传入形成中的作用已得到很好的证实，但它在毛细胞成熟中的可能参与仍不清楚。在这里，我们发现杂合 Gata3 缺失小鼠（Gata3 ）的外毛细胞（OHC）分化正常，但数量明显较低。相比之下，内毛细胞（IHC）正常存活，但它们不能获得成人基底外侧膜电流，保留前听力电流和传出神经支配模式，并且有更少的连接蛋白突触。由 otoferlin-cre 重组酶驱动的 Gata3 在内耳细胞中的靶向缺失（Gata3 otof-cre ）不会影响 OHC 或 IHC 传入突触的数量，但会导致与在 Gata3 小鼠中观察到的相似的 IHC 成熟失败。Gata3 otof-cre 小鼠的听觉脑干反应显示进行性听力损失，6-7 个月时变得严重，而畸变产物耳声发射在这个年龄之前与对照动物没有不同。我们的结果以及现有的数据表明，Gata3 在内耳发育的不同细胞类型中具有特定的、互补的功能，并且其在感觉上皮中的持续表达协调了生理发育和神经连接的关键方面。此外，我们的工作表明，人类甲状旁腺功能减退症、耳聋和肾脏异常（HDR）综合征的听力损失不仅源于 IHC 的功能缺陷，还源于 OHC 以及传入和传出神经元的功能丧失。
