RESUMO
As the sensory receptor cells in vertebrate inner ear and lateral lines, hair cells are characterized by the hair bundle that consists of one tubulin-based kinocilium and dozens of actin-based stereocilia on the apical surface of each hair cell. Hair cell development is tightly regulated, and deficits in this process usually lead to hearing loss and/or balance dysfunctions. RNA-binding motif protein 24 (RBM24) is an RNA-binding protein that is specifically expressed in the hair cells in the inner ear. Previously, we showed that RBM24 affects hair cell development in zebrafish by regulating messenger RNA (mRNA) stability. In the present work, we further investigate the role of RBM24 in hearing and balance using conditional knockout mice. Our results show that Rbm24 knockout results in severe hearing and balance deficits. Hair cell development is significantly affected in Rbm24 knockout cochlea, as the hair bundles are poorly developed and eventually degenerated. Hair bundle disorganization is also observed in Rbm24 knockout vestibular hair cells, although to a lesser extent. Consistently, significant hair cell loss is observed in the cochlea but not vestibule. RNAseq analysis identified several genes whose mRNA stability or pre-mRNA alternative splicing is affected by Rbm24 knockout. Among them are Cdh23, Pcdh15, and Myo7a, which have been shown to play important roles in stereocilia development as well as mechano-electrical transduction. Taken together, our present work suggests that RBM24 is required for mouse hair cell development through regulating pre-mRNA alternative splicing as well as mRNA stability.
Assuntos
Processamento Alternativo , Células Ciliadas Auditivas , Precursores de RNA , Animais , Camundongos , Processamento Alternativo/genética , Caderinas/genética , Camundongos Knockout , Precursores de RNA/genética , Precursores de RNA/metabolismo , Estabilidade de RNA/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Peixe-Zebra , Células Ciliadas Auditivas/fisiologiaRESUMO
Stress granules (SGs) are formed when untranslated messenger ribonucleoproteins (mRNPs) accumulate in cells under stress, and are thought to minimize stress-induced damage and promote cell survival. RBM24 (RNA-binding motif protein 24) is an RNA-binding protein that plays pivotal roles in regulating the stability or translation initiation of target mRNAs as well as alternative splicing of target pre-mRNAs. Its important physiological functions are highlighted by the fact that Rbm24 knockout mice or zebrafish suffer from dysfunction of heart, eye, and inner ear. Here we show that RBM24 is recruited into SGs under various stress conditions, suggesting that it might protect its target RNAs in cells under stress. However, SG formation is unaffected when Rbm24 expression is down-regulated. Nevertheless, RBM24 overexpression in cultured cells is sufficient to induce SG formation, suggesting that RBM24 might play an important role in SG formation. In conclusion, our present work reveals that RBM24 is a SG component, which implies that RBM24 could protect its target mRNAs in stressed cells.
