Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, 210096, China; Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, 210096, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
Neuropharmacology. 2019 Jan;144:43-57. doi: 10.1016/j.neuropharm.2018.10.021. Epub 2018 Oct 15.
The development of therapeutic interventions for hearing loss requires a detailed understanding of the genes and proteins involved in hearing. The FOXG1 protein plays an important role in early neural development and in a variety of neurodevelopmental disorders. Previous studies have shown that there are severe deformities in the inner ear in Foxg1 knockout mice, but due to the postnatal lethality of Foxg1 knockout mice, the role of FOXG1 in hair cell (HC) development and survival during the postnatal period has not been investigated. In this study, we took advantage of transgenic mice that have a specific knockout of Foxg1 in HCs, thus allowing us to explore the role of FOXG1 in postnatal HC development and survival. In the Foxg1 conditional knockout (CKO) HCs, an extra row of HCs appeared in the apical turn of the cochlea and some parts of the middle turn at postnatal day (P)1 and P7; however, these HCs gradually underwent apoptosis, and the HC number was significantly decreased by P21. Auditory brainstem response tests showed that the Foxg1 CKO mice had lost their hearing by P30. The RNA-Seq results and the qPCR verification both showed that the Wnt, Notch, IGF, EGF, and Hippo signaling pathways were down-regulated in the HCs of Foxg1 CKO mice. The significant down-regulation of the Notch signaling pathway might be the reason for the increased numbers of HCs in the cochleae of Foxg1 CKO mice at P1 and P7, while the down-regulation of the Wnt, IGF, and EGF signaling pathways might lead to subsequent HC apoptosis. Together, these results indicate that knockout of Foxg1 induces an extra row of HCs via Notch signaling inhibition and induces subsequent apoptosis of these HCs by inhibiting the Wnt, IGF, and EGF signaling pathways. This study thus provides new evidence for the function and mechanism of FOXG1 in HC development and survival in mice.
治疗听力损失的干预措施的发展需要详细了解参与听力的基因和蛋白质。FOXG1 蛋白在早期神经发育和多种神经发育障碍中发挥重要作用。先前的研究表明，Foxg1 基因敲除小鼠的内耳严重畸形，但由于 Foxg1 基因敲除小鼠的出生后致死性，FOXG1 在出生后时期毛细胞（HC）发育和存活中的作用尚未得到研究。在这项研究中，我们利用在内耳 HC 中特异性敲除 Foxg1 的转基因小鼠，从而能够探索 FOXG1 在出生后 HC 发育和存活中的作用。在 Foxg1 条件性敲除（CKO）HC 中，在出生后第 1 天（P1）和第 7 天（P7），耳蜗的顶圈和中部的某些部位出现了额外的 HC 排；然而，这些 HC 逐渐凋亡，HC 数量在 P21 时显著减少。听觉脑干反应测试显示，Foxg1 CKO 小鼠在 P30 时已经失去听力。RNA-Seq 结果和 qPCR 验证均表明，Foxg1 CKO 小鼠的 HC 中 Wnt、Notch、IGF、EGF 和 Hippo 信号通路下调。Notch 信号通路的显著下调可能是 Foxg1 CKO 小鼠耳蜗中 HC 数量在 P1 和 P7 时增加的原因，而 Wnt、IGF 和 EGF 信号通路的下调可能导致随后的 HC 凋亡。总之，这些结果表明，Foxg1 的敲除通过 Notch 信号抑制诱导额外的 HC 排，并通过抑制 Wnt、IGF 和 EGF 信号通路诱导随后这些 HC 的凋亡。这项研究为 FOXG1 在小鼠 HC 发育和存活中的功能和机制提供了新的证据。
