The RNA-binding protein TRIM71 is essential for hearing in humans and mice and times auditory sensory organ development
Abstract
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 TGFβ-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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Xiao-Jun Li
Charles Morgan
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Phan Q. Duy
Lale Evsen
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Le T. Hao
Department of Neurosurgery, Yale University School of Medicine
Roxane Machavoine
Centre de Référence Surdités Génétiques, Service de Médecine génomique des Maladies Rares, UF Morphogenèse et Développement, Hôpital Necker, Assistance Publique-Hopitaux de Paris, Université Paris Cité
Kahina Belhous
Service de Radiologie Pédiatrique, Hôpital Necker, Assistance Publique-Hopitaux de Paris, Université Paris Cité
Sylvain Ernest
INSERM UMR1163, Institut Imagine, Université Paris Cité
Françoise Denoyelle
Service d'Oto-rhino-laryngologie Pédiatrique et de Chirurgie Cervico Faciale, Hôpital Necker, Assistance Publique-Hopitaux de Paris, Université Paris Cité
Cyril Mignot
Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière and Hôpital Trousseau and Centre de Référence Maladies Rares Déficiences Intellectuelles de Causes Rares, Assistance Publique-Hopitaux de Paris Sorbonne Université
Frederic Brioude
INSERM, Centre de Recherche Saint-Antoine, Assistance Publique-Hopitaux de Paris, Hôpital Trousseau, Sorbonne Université
Marine Parodi
Service d'Oto-rhino-laryngologie Pédiatrique et de Chirurgie Cervico Faciale, Hôpital Necker, Assistance Publique-Hopitaux de Paris, Université Paris Cité
Lin Li
He Huang
Prathamesh T. Nadar Ponniah
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
Waldemar Kolanus
Molecular Immunology and Cell Biology, Life and Medical Sciences Institute, University of Bonn
Kristopher T. Kahle
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
Sandrine Marlin
Centre de Référence Surdités Génétiques, Service de Médecine génomique des Maladies Rares, UF Morphogenèse et Développement, Hôpital Necker, Assistance Publique-Hopitaux de Paris, Université Paris Cité
Angelika Doetzlhofer
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine