A Nesprin-4/kinesin-1 cargo model for nuclear positioning in cochlear outer hair cells

被引:8
作者
Taiber, Shahar [1 ,2 ,3 ]
Gozlan, Oren [3 ]
Cohen, Roie [3 ]
Andrade, Leonardo R. [4 ]
Gregory, Ellen F. [5 ]
Starr, Daniel A. [5 ]
Moran, Yehu [6 ]
Hipp, Rebecca [7 ]
Kelley, Matthew W. [7 ]
Manor, Uri [4 ]
Sprinzak, David [3 ]
Avraham, Karen B. [1 ,2 ]
机构
[1] Tel Aviv Univ, Fac Med, Dept Human Mol Genet & Biochem, Tel Aviv, Israel
[2] Tel Aviv Univ, Sagol Sch Neurosci, Tel Aviv, Israel
[3] Tel Aviv Univ, George S Wise Fac Life Sci, Sch Neurobiol Biochem & Biophys, Tel Aviv, Israel
[4] Salk Inst Biol Studies, Waitt Adv Biophoton Ctr, La Jolla, CA USA
[5] Univ Calif Davis, Dept Mol & Cellular Biol, Davis, CA USA
[6] Hebrew Univ Jerusalem, Dept Ecol Evolut & Behav, Alexander Silberman Inst Life Sci, Fac Sci, Jerusalem, Israel
[7] Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Bethesda, MD USA
来源
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY | 2022年 / 10卷
基金
美国国家卫生研究院; 以色列科学基金会; 欧洲研究理事会;
关键词
Nesprin; LINC complex; KASH; hair cells; cochlea; MEMBRANE PROTEIN; LINC; KINESIN-1; MUSCLE; ELECTROMOTILITY; CRISPR-CAS9; EXPRESSION; ANCHORAGE; CYTOPLASM; MIGRATION;
D O I
10.3389/fcell.2022.974168
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Nuclear positioning is important for the functionality of many cell types and is mediated by interactions of cytoskeletal elements and nucleoskeleton proteins. Nesprin proteins, part of the linker of nucleoskeleton and cytoskeleton (LINC) complex, have been shown to participate in nuclear positioning in multiple cell types. Outer hair cells (OHCs) in the inner ear are specialized sensory epithelial cells that utilize somatic electromotility to amplify auditory signals in the cochlea. Recently, Nesprin-4 (encoded by Syne4) was shown to play a crucial role in nuclear positioning in OHCs. Syne4 deficiency in humans and mice leads to mislocalization of the OHC nuclei and cell death resulting in deafness. However, it is unknown how Nesprin-4 mediates the position of the nucleus, and which other molecular components are involved in this process. Here, we show that the interaction of Nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. Using in vivo AAV gene delivery, we show that this interaction is critical for nuclear positioning and hearing in mice. Nuclear mislocalization and cell death of OHCs coincide with the onset of hearing and electromotility and are solely restricted to outer, but not inner, hair cells. Likewise, the C. elegans functional homolog of Nesprin-4, UNC-83, uses a similar motif to mediate interactions between migrating nuclei and kinesin-1. Overall, our results suggest that OHCs require unique cellular machinery for proper nuclear positioning at the onset of electromotility. This machinery relies on the interaction between Nesprin-4 and kinesin-1 motors supporting a microtubule cargo model for nuclear positioning.
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页数:15
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