Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal
Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal
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DOI：
10.1073/pnas.2000175117
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发表时间：
2020-06-16
影响因子：
11.1
通讯作者：
Segil, Neil
中科院分区：
文献类型：
--
作者：
Gnedeva, Ksenia;Wang, Xizi;Segil, Neil
器官生长和模式的精确控制是通过祖细胞自我更新和分化的平衡调节来实现的。在听觉感觉上皮（柯蒂氏器官）中，在感觉受体细胞分化开始之前，祖细胞以 E12.5 和 E14.5 之间的协调波退出细胞周期，使其成为研究控制增殖和分化之间切换的分子机制的独特系统。在这里，我们将 Yap/Tead 复合体确定为 Corti 祖细胞器官中自我更新基因网络的关键调节因子。我们发现 Tead 转录因子直接与许多干性和细胞周期相关基因的假定调控元件结合。我们还表明，Tead 共激活蛋白 Yap 在耳蜗管的 Sox2 阳性结构域中被特异性降解，导致 Tead 基因靶标下调。此外，内耳中 Yap 基因的条件性缺失会导致形成明显较小的听觉和前庭感觉上皮，而 Yap 组成型活性版本 Yap5SA 的条件性过度表达足以阻止细胞周期退出并延长感觉组织的生长。我们还表明，体内出生后内耳感觉上皮细胞中 Yap5SA 的病毒基因传递可在毛细胞丢失后驱动细胞周期重新进入。总而言之，这些数据强调了 Yap/Tead 转录因子复合物在发育过程中维持内耳祖细胞的关键作用，并提出了诱导感觉细胞再生的新策略。
Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium-the organ of Corti-progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.