The RNA- binding protein TRIM71 is essential for hearing in humans and mice and times auditory sensory organ development

• 成果类型: Article
• 署名作者: Li, Xiao - Jun; Morgan, Charles; Duy, Phan Q.; Evsen, Lale; Hao, Le T.; Machavoine, Roxane; Belhous, Kahina; Ernest, Sylvain; Denoyelle, Francoise; Mignot, Cyril; Brioude, Frederic; Parodi, Marine; Li, Lin; Huang, He; Ponniah, Prathamesh T. Nadar; Kolanus, Waldemar; Kahle, Kristopher T.; Marlin, Sandrine; Doetzlhofer, Angelika
• 署名单位: Johns Hopkins University; Xi'an Jiaotong University; Yale University; Yale University; Yale University; Yale University; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Necker-Enfants Malades - APHP; Hopital Universitaire Saint-Louis - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Saint-Louis - APHP; Hopital Universitaire Necker-Enfants Malades - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Saint-Louis - APHP; Hopital Universitaire Necker-Enfants Malades - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Saint-Louis - APHP; Sorbonne Universite; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Saint-Louis - APHP; Sorbonne Universite; Hopital Universitaire Armand-Trousseau - APHP; Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Saint-Louis - APHP; Sorbonne Universite; Institut National de la Sante et de la Recherche Medicale (Inserm); Assistance Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital Universitaire Saint-Louis - APHP; Sorbonne Universite; Hopital Universitaire Armand-Trousseau - APHP; University of Bonn; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Johns Hopkins University; University of Sydney; Kolling Institute of Medical Research
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11926
• DOI: 10.1073/pnas.2505811122
• 发表日期: 2025-09-09
• 关键词: inner-ear; let-7 microrna; cells; gene; primordium; generation; expression; insights; homolog; PATHWAY

摘要

The RNA-binding protein TRIM71 is essential for brain development, and recent genetic studies in humans have identified TRIM71 as a risk gene for congenital hydrocephal-us (CH). Here, we show that monoallelic missense mutations in TRIM71 are associated with hearing loss (HL) and inner ear aplasia in humans. Utilizing conditional Trim71 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 Trim71 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 Trim71-deficient cochlear progenitor cells identifies Inhba and Tgfbr2 as targets of TRIM71 repression, and our analysis of Inhba-Tgfbr1 double knockout mice indicates that TRIM71 maintains hair cell progenitors in a proliferative and undifferentiated state by restricting TGF beta-type signaling. Characterization of hair cells and their associated neurons in adult Trim71 knockout mice revealed reduced presynaptic terminals and neuronal degeneration in the outer hair cell region, providing a basis for the observed hearing deficits in Trim71 knockout mice.