Alternative Splicing of Three Genes Encoding Mechanotransduction-Complex Proteins in Auditory Hair Cells

Zhou, Zijing; Yu, Xiaojie; Jiang, Biaobin; Feng, Wanying; Tian, Ye; Liu, Zhiyong; Wang, Jiguang; Huang, Pingbo

doi:10.1523/eneuro.0381-20.2020

Cited by 4 publications

(3 citation statements)

References 38 publications

(71 reference statements)

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“…As we previously reported [23], and others also confirmed using hTMC1 [28], among the two major splice variants for mTmc1 mRNA, mTmc1ex1 is the splice variant which can translate the protein of mTMC1. Therefore, we used mTmc1ex1 as the cDNA of mTmc1 in this study.…”

Section: Accumulation Of the N-terminal Region Of Heterologously-expr...supporting

confidence: 76%

The cytosolic N-terminal region of heterologously-expressed transmembrane channel-like protein 1 (TMC1) can be cleaved in HEK293 cells

Yamaguchi,

Kamino,

Hamamura

et al. 2023

PLoS ONE

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Transmembrane channel-like protein 1 (TMC1) is a transmembrane protein forming mechano-electrical transduction (MET) channel, which transduces mechanical stimuli into electrical signals at the top of stereocilia of hair cells in the inner ear. As an unexpected phenomenon, we found that the cytosolic N-terminal (Nt) region of heterologously-expressed mouse TMC1 (mTMC1) was localized in nuclei of a small population of the transfected HEK293 cells. This raised the possibility that the Nt region of heterologously-expressed mTMC1 was cleaved and transported into the nucleus. To confirm the cleavage, we performed western blot analyses. The results revealed that at least a fragment of the Nt region was produced from heterologously-expressed mTMC1. Site-directed mutagenesis experiments identified amino acid residues which were required to produce the fragment. The accumulation of the heterologously-expressed Nt fragment into the nuclei depended on nuclear localization signals within the Nt region. Furthermore, a structural comparison showed a similarity between the Nt region of mTMC1 and basic region leucine zipper (bZIP) transcription factors. However, transcriptome analyses using a next-generation sequencer showed that the heterologously-expression of the Nt fragment of mTMC1 hardly altered expression levels of genes. Although it is still unknown what is the precise mechanism and the physiological significance of this cleavage, these results showed that the cytosolic Nt region of heterologously-expressed mTMC1 could be cleaved in HEK293 cells. Therefore, it should be taken into account that the cleavage of Nt region might influence the functional analysis of TMC1 by the heterologous-expression system using HEK293 cells.

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Section: Accumulation Of the N-terminal Region Of Heterologously-expr...supporting

confidence: 76%

The cytosolic N-terminal region of heterologously-expressed transmembrane channel-like protein 1 (TMC1) can be cleaved in HEK293 cells

Yamaguchi,

Kamino,

Hamamura

et al. 2023

PLoS ONE

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“…Four AS events were identified in the Tmc1, Lhfpl5, and Tmie genes and subsequently verified through RT-PCR. Three of these events occurred in significantly higher frequencies in OHCs than in IHCs (Zhou et al, 2021). Although they avoided speculation as to the possible implications of these data, the authors of the study did demonstrate that data generated via high-throughput pipelines can help identify potentially important AS events.…”

Section: Cell Type-specific Splicing In the Cochleamentioning

confidence: 96%

“…Transcriptomes of 4 cell types have been characterized using this method (Liu et al, 2018). Zhou et al (2021) probed this database for previously unknown splice variants of MET machinery components. Four AS events were identified in the Tmc1, Lhfpl5, and Tmie genes and subsequently verified through RT-PCR.…”

Section: Cell Type-specific Splicing In the Cochleamentioning

confidence: 99%

Alternative splicing in shaping the molecular landscape of the cochlea

Kim

Koo²,

Bok³

2023

Front. Cell Dev. Biol.

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The cochlea is a complex organ comprising diverse cell types with highly specialized morphology and function. Until now, the molecular underpinnings of its specializations have mostly been studied from a transcriptional perspective, but accumulating evidence points to post-transcriptional regulation as a major source of molecular diversity. Alternative splicing is one of the most prevalent and well-characterized post-transcriptional regulatory mechanisms. Many molecules important for hearing, such as cadherin 23 or harmonin, undergo alternative splicing to produce functionally distinct isoforms. Some isoforms are expressed specifically in the cochlea, while some show differential expression across the various cochlear cell types and anatomical regions. Clinical phenotypes that arise from mutations affecting specific splice variants testify to the functional relevance of these isoforms. All these clues point to an essential role for alternative splicing in shaping the unique molecular landscape of the cochlea. Although the regulatory mechanisms controlling alternative splicing in the cochlea are poorly characterized, there are animal models with defective splicing regulators that demonstrate the importance of RNA-binding proteins in maintaining cochlear function and cell survival. Recent technological breakthroughs offer exciting prospects for overcoming some of the long-standing hurdles that have complicated the analysis of alternative splicing in the cochlea. Efforts toward this end will help clarify how the remarkable diversity of the cochlear transcriptome is both established and maintained.

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Comparative transcriptome profiling reveals RNA splicing alterations and biological function in patients exposed to occupational noise

Chen,

Shao,

Zhao

et al. 2023

Environ Sci Pollut Res

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Alternative Splicing of Three Genes Encoding Mechanotransduction-Complex Proteins in Auditory Hair Cells

Abstract: Visual Abstract

Cited by 4 publications

References 38 publications

The cytosolic N-terminal region of heterologously-expressed transmembrane channel-like protein 1 (TMC1) can be cleaved in HEK293 cells

The cytosolic N-terminal region of heterologously-expressed transmembrane channel-like protein 1 (TMC1) can be cleaved in HEK293 cells

Alternative splicing in shaping the molecular landscape of the cochlea

Comparative transcriptome profiling reveals RNA splicing alterations and biological function in patients exposed to occupational noise

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