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

Shahar Taiber, Oren Gozlan, Roie Cohen, Leonardo R. Andrade, Ellen F. Gregory, Daniel A. Starr, Yehu Moran, Rebecca Hipp, Matthew W. Kelley, Uri Manor, David Sprinzak, Karen B. Avraham*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish
Article number974168
JournalFrontiers in Cell and Developmental Biology
Volume10
DOIs
StatePublished - 23 Sep 2022

Funding

FundersFunder number
Grohne FoundationP30 014195
National Science Foundation2014862
National Institutes of Health
National Institute on Deafness and Other Communication DisordersDC000059, R01DC011835
National Institute of General Medical SciencesR35GM134859
Larry L. Hillblom FoundationR21 DC018237
Waitt Foundation
Horizon 2020 Framework Programme682161
European Research Council
United States-Israel Binational Science Foundation01027150
Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
Israel Science Foundation1763/20
Tel Aviv University

    Keywords

    • KASH
    • LINC complex
    • Nesprin
    • cochlea
    • hair cells

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