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

The RNA-binding protein TRIM71 is essential for brain development, and recent genetic studies in humans have identified <i>TRIM71</i> as a risk gene for congenital hydrocephal-us (CH). Here, we show that monoallelic missense mutations in <i>TRIM71</i> are associated with hearing loss (HL) and inner ear aplasia in humans. Utilizing conditional <i>Trim71</i> 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 <i>Trim71</i> 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 <i>Trim71</i>-deficient cochlear progenitor cells identifies <i>Inhba</i> and <i>Tgfbr2</i> as targets of TRIM71 repression, and our analysis of <i>Inhba-Tgfbr1</i> 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 <i>Trim71</i> knockout mice revealed reduced presynaptic terminals and neuronal degeneration in the outer hair cell region, providing a basis for the observed hearing deficits in <i>Trim71</i> knockout mice.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-09-02
DOI
https://doi.org/10.1073/pnas.2505811122
Primary Topic
Hearing, Cochlea, Tinnitus, Genetics
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Marine Parodi, Kahina Belhous, Waldemar Kolanus, Sylvain Ernest et al.
1 links
Proceedings of the National Academy of Sciences
Hearing, Cochlea, Tinnitus, Genetics
article

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

Marine Parodi, Kahina Belhous, Waldemar Kolanus, Sylvain Ernest, He Huang, Sandrine Marlin, Angelika Doetzlhofer, C. Lloyd Morgan, Lale Evsen, Kristopher T. Kahle, Roxane Machavoine, Cyril Mignot, Françoise Denoyelle, Phan Q. Duy, Frédéric Brioude, Prathamesh T. Nadar Ponniah, Xiaojun Li, Lin Li, Le Hao
article en

Abstract

The RNA-binding protein TRIM71 is essential for brain development, and recent genetic studies in humans have identified <i>TRIM71</i> as a risk gene for congenital hydrocephal-us (CH). Here, we show that monoallelic missense mutations in <i>TRIM71</i> are associated with hearing loss (HL) and inner ear aplasia in humans. Utilizing conditional <i>Trim71</i> 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 <i>Trim71</i> 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 <i>Trim71</i>-deficient cochlear progenitor cells identifies <i>Inhba</i> and <i>Tgfbr2</i> as targets of TRIM71 repression, and our analysis of <i>Inhba-Tgfbr1</i> 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 <i>Trim71</i> knockout mice revealed reduced presynaptic terminals and neuronal degeneration in the outer hair cell region, providing a basis for the observed hearing deficits in <i>Trim71</i> knockout mice.

Proceedings of the National Academy of SciencesVol. 122(36)
Broad Institute (US), Hôpital Necker-Enfants Malades (FR), Boston Children's Hospital (US), University of Bonn (DE), Harvard University (US), Johns Hopkins University (US), Inserm (FR), Université Paris Cité (FR), Johns Hopkins Medicine (US), Yale University (US), Sorbonne Université (FR), Massachusetts General Hospital (US), Assistance Publique – Hôpitaux de Paris (FR), NeuroDevelopment Center (US), Neuroscience Institute (IT), Centre de Recherche Saint-Antoine (FR), Life & Brain (Germany) (DE), Institut des Maladies Génétiques Imagine (FR), Massachusetts Institute of Technology (US), Xi'an Jiaotong University (CN)
Agence Nationale de la Recherche, National Institute on Aging, National Institute on Deafness and Other Communication Disorders, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 77%
Hearing, Cochlea, Tinnitus, Genetics
DOIOpen Access PDFOpenAlex
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