Rbm24 regulates inner-ear-specific alternative splicing and is essential for maintaining auditory and motor coordination

Zheng, Longqing; Yuan, Huijun; Zhang, Mengkai; Wang, Cuicui; Cai, Xue-Min; Liu, Jing; Xiao-hong, XU

doi:10.1080/15476286.2020.1817265

Cited by 18 publications

(8 citation statements)

References 49 publications

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“…27 Hence, Rbm24-inducible knockout mouse model was constructed (Figure S1A-D). 28 Tamoxifen (100 mg/kg daily for 5 days) was injected intraperitoneally into 8-week-old CreERT2-Rbm24 loxp/loxp mice (N = 32) to generate Rbm24 conditional knockout mice. Wild type (WT) mice were administrated with the same dose of tamoxifen (Figure 1A).…”

Section: Rbm24-knockout Mice Develop Spontaneous Colorectal Adenomasmentioning

confidence: 99%

RNA‐binding protein RBM24 represses colorectal tumourigenesis by stabilising PTEN mRNA

Xia

Liu

et al. 2021

Clinical & Translational Med

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Background RNA‐binding motif protein 24 (RBM24) functions as a splicing regulator, which is critical for organ development and is dysregulated in human cancers. Here, we aim to uncover the biological function of RBM24 in colorectal tumourigenesis. Methods Xenograft tumour model, Rbm24 knockout and Apc min/+ mouse models were utilised. Colorectal cancer cells overexpressing or silencing RBM24 were established. RNA immunoprecipitation (RIP) assay was conducted to detect protein‐RNA associations. Gene expression was measured by immunohistochemistry, western blotting, or quantitative PCR (qPCR). Results Rbm24‐knockout mice developed spontaneous colorectal adenomas with lower expression of phosphatase and tensin homolog (PTEN). Immunohistochemical staining for the proliferation markers Ki‐67 and pHH3 and BrdU assay showed intestinal hyperplasia in Rbm24‐knockout mice compared to wild‐type mice. RBM24 expression in colorectal adenoma tissues of Apc min/+ mouse was downregulated compared with adjacent normal samples and was positively correlated with PTEN expression. In vitro, RBM24 overexpression suppressed cell proliferation, migration, invasion and increased sensitivity to 5‐FU or cisplatin in CRC cells. Mechanistically, RBM24 maintained PTEN mRNA stability by directly binding to the GT‐rich region at positions 8101–8251 in the 3′‐UTR of PTEN mRNA, prolonging the half‐life of PTEN mRNA, thereby increasing PTEN expression. Hence, low expression of RBM24 downregulated PTEN mRNA, causing the activation of PI3K‐Akt signalling in CRC cells. Furthermore, RBM24 expression in CRC tissues was lower than adjacent normal samples. RBM24 expression was positively correlated with PTEN expression and negatively correlated with Ki‐67 level. CRC patients with high RBM24 expression had a favourable outcome. Conclusions Taken together, RBM24 expression is markedly lower in colorectal tumours than in para‐carcinoma tissues. Rbm24‐knockout mice develop spontaneous colorectal adenomas. RBM24 directly binds and stabilises PTEN mRNA, which could cause the suppression of CRC cell proliferation, migration and invasion, thereby repressing colorectal tumourigenesis. These findings support the tumour‐suppressive role of RBM24. Targeting RBM24 holds strong promise for the diagnosis and treatment of CRC.

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Section: Rbm24-knockout Mice Develop Spontaneous Colorectal Adenomasmentioning

confidence: 99%

RNA‐binding protein RBM24 represses colorectal tumourigenesis by stabilising PTEN mRNA

Xia

Liu

et al. 2021

Clinical & Translational Med

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“…Rbm24 -/-OHCs, but not IHCs, are degenerated by P19 [37]. RBM24 is also involved in mRNA stability and pre-mRNA alternative splicing of several genes, including Cdh23 and Pcdh15, which are crucial for the development of HC stereocilia [55][56][57]. Our study also revealed that GATA3 expression is decreased and IKZF2 expression is increased in OHCs in the absence of RBM24, which could be a direct or indirect effect of RBM24 loss.…”

Section: Roles Of Rbm24 and Its Regulation During Cochlear Hc Develop...mentioning

confidence: 54%

Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining cochlear hair cell survival

Wang

Liu

2023

Preprint

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Mammals have limited sound receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the molecular mechanisms underlying how to maintain HC survival is crucial to prevent hearing impairment. The Pou4f3-/- or Gfi1-/- HCs initially form but rapidly degenerate, whereas Rbm24-/- HCs degenerate much later. It remains elusive about the transcriptional cascades among Pou4f3, Gfi1 and Rbm24. Here, we demonstrate that Rbm24 expression is completely repressed in Pou4f3-/- HCs, but its expression is not altered in Gfi1-/- HCs. Moreover, both Pou4f3 and Gfi1 expressions are intact in Rbm24-/- HCs. Moreover, by the in vivo mouse transgenic reporter assays, we identify three Rbm24 enhancers to which Pou4f3 binds. Finally, we test whether Rbm24 restoration can alleviate degeneration of Pou4f3-/- HCs. Our in vivo genetic assay shows that ectopic Rbm24 alone is unable to stop Pou4f3-/- HCs from undergoing degeneration. Collectively, our study provides new molecular and genetic insights into how HC survival is regulated.

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“…Nevertheless, our previous work revealed that the otic vesicle is largely unaffected in conventional Rbm24a knockout zebrafish, suggesting that RBM24 is not necessary for early inner ear development at least in zebrafish (Zhang et al, 2020). Recently, Zheng and colleagues reported that Tamoxifen‐induced global knockout of Rbm24 in adult mice causes hair cell degeneration, suggesting that RBM24 is necessary for hair cell maintenance mainly through regulating alternative splicing (Zheng, Yuan, et al, 2021). Our present work reveals that RBM24 is also required for hair cell development.…”

Section: Discussionmentioning

confidence: 99%

RBM24 is required for mouse hair cell development through regulating pre‐mRNA alternative splicing and mRNA stability

Wang

Zhang

Peng

et al. 2023

Journal Cellular Physiology

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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.

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Rbm24 regulates inner-ear-specific alternative splicing and is essential for maintaining auditory and motor coordination

Cited by 18 publications

References 49 publications

RNA‐binding protein RBM24 represses colorectal tumourigenesis by stabilising PTEN mRNA

RNA‐binding protein RBM24 represses colorectal tumourigenesis by stabilising PTEN mRNA

Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining cochlear hair cell survival

RBM24 is required for mouse hair cell development through regulating pre‐mRNA alternative splicing and mRNA stability

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