Li Xiao-Jun, Morgan Charles, Duy Phan Q, Evsen Lale, Hao Le T, Machavoine Roxane, Belhous Kahina, Ernest Sylvain, Denoyelle Françoise, Mignot Cyril, Brioude Frederic, Parodi Marine, Li Lin, Huang He, Nadar Ponniah Prathamesh T, Kolanus Waldemar, Kahle Kristopher T, Marlin Sandrine, Doetzlhofer Angelika
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
Proc Natl Acad Sci U S A. 2025 Sep 9;122(36):e2505811122. doi: 10.1073/pnas.2505811122. Epub 2025 Sep 2.
The RNA-binding protein TRIM71 is essential for brain development, and recent genetic studies in humans have identified as a risk gene for congenital hydrocephal-us (CH). Here, we show that monoallelic missense mutations in are associated with hearing loss (HL) and inner ear aplasia in humans. Utilizing conditional knockout mice carrying a CH and HL-associated mutation, we demonstrate that loss of TRIM71 function during early otic development (embryonic day 9 to 10) causes severe HL. While inner ear morphogenesis occurs normally in knockout mice, we find that early otic loss of TRIM71 function disrupts the highly stereotyped timing of cell cycle exit and differentiation within the inner ear auditory sensory organ (cochlea), resulting in the premature formation and innervation of mechanosensory hair cells. Transcriptomic profiling of -deficient cochlear progenitor cells identifies and as targets of TRIM71 repression, and our analysis of double knockout mice indicates that TRIM71 maintains hair cell progenitors in a proliferative and undifferentiated state by restricting TGFβ-type signaling. Characterization of hair cells and their associated neurons in adult knockout mice revealed reduced presynaptic terminals and neuronal degeneration in the outer hair cell region, providing a basis for the observed hearing deficits in knockout mice.
RNA结合蛋白TRIM71对大脑发育至关重要，最近的人类遗传学研究已将其确定为先天性脑积水（CH）的风险基因。在此，我们表明TRIM71的单等位基因错义突变与人类听力损失（HL）和内耳发育不全有关。利用携带与CH和HL相关突变的条件性敲除小鼠，我们证明在早期耳发育（胚胎第9至10天）期间TRIM71功能丧失会导致严重的HL。虽然敲除小鼠的内耳形态发生正常，但我们发现TRIM71功能在早期耳中的丧失会破坏内耳听觉感觉器官（耳蜗）内细胞周期退出和分化的高度刻板时间，导致机械感觉毛细胞过早形成和神经支配。TRIM71缺陷的耳蜗祖细胞的转录组分析确定Fgfr1和Fgfr2为TRIM71抑制的靶标，并且我们对Fgfr1和Fgfr2双敲除小鼠的分析表明，TRIM71通过限制TGFβ型信号传导将毛细胞祖细胞维持在增殖和未分化状态。成年敲除小鼠中毛细胞及其相关神经元的特征表明，外毛细胞区域的突触前终末减少和神经元变性，这为敲除小鼠中观察到的听力缺陷提供了基础。
