KLC4 shapes axon arbors during development and mediates adult behavior

  1. Elizabeth M Haynes
  2. Korri H Burnett
  3. Jiaye He
  4. Marcel W Jean-Pierre
  5. Martin Jarzyna
  6. Kevin W Eliceiri
  7. Jan Huisken
  8. Mary C Halloran  Is a corresponding author
  1. University of Wisconsin-Madison, United States
  2. National Innovation Center for Advanced Medical Devices, China
  3. Morgridge Institute for Research, United States

Abstract

Development of elaborate and polarized neuronal morphology requires precisely regulated transport of cellular cargos by motor proteins such as kinesin-1. Kinesin-1 has numerous cellular cargos which must be delivered to unique neuronal compartments. The process by which this motor selectively transports and delivers cargo to regulate neuronal morphogenesis is poorly understood, although the cargo-binding kinesin light chain (KLC) subunits contribute to specificity. Our work implicates one such subunit, KLC4, as an essential regulator of axon branching and arborization pattern of sensory neurons during development. Using live imaging approaches in klc4 mutant zebrafish, we show that KLC4 is required for stabilization of nascent axon branches, proper microtubule (MT) dynamics, and endosomal transport. Furthermore, KLC4 is required for proper tiling of peripheral axon arbors: in klc4 mutants, peripheral axons showed abnormal fasciculation, a behavior characteristic of central axons. This result suggests that KLC4 patterns axonal compartments and helps establish molecular differences between central and peripheral axons. Finally, we find that klc4 mutant larva are hypersensitive to touch and adults show anxiety-like behavior in a novel tank test, implicating klc4 as a new gene involved in stress response circuits.

Data availability

All data generated or analyzed in this study are included in the manuscript and supporting files. Source Data files have been provided for Figures 1-12.

Article and author information

Author details

  1. Elizabeth M Haynes

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  2. Korri H Burnett

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  3. Jiaye He

    National Innovation Center for Advanced Medical Devices, Shenzen, China
    Competing interests
    No competing interests declared.
  4. Marcel W Jean-Pierre

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  5. Martin Jarzyna

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    Competing interests
    No competing interests declared.
  6. Kevin W Eliceiri

    Center for Quantitative Cell Imaging, University of Wisconsin-Madison, Madison, United States
    Competing interests
    Kevin W Eliceiri, is a consultant for Bruker, the manufacturer of the Opterra swept field confocal used in this work..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8678-670X
  7. Jan Huisken

    Morgridge Institute for Research, Madison, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7250-3756
  8. Mary C Halloran

    Department of Integrative Biology, University of Wisconsin-Madison, Madison, United States
    For correspondence
    mchalloran@wisc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6086-5928

Funding

National Institutes of Health (R01 NS086934)

  • Mary C Halloran

National Institutes of Health (R21 NS116326)

  • Mary C Halloran

National Institutes of Health (F32 NS098689)

  • Elizabeth M Haynes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animals were handled according to approved institutional animal care and use committee protocols of the University of Wisconsin (protocols L005692 and L005704).

Copyright

© 2022, Haynes et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,650
    views
  • 244
    downloads
  • 7
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Elizabeth M Haynes
  2. Korri H Burnett
  3. Jiaye He
  4. Marcel W Jean-Pierre
  5. Martin Jarzyna
  6. Kevin W Eliceiri
  7. Jan Huisken
  8. Mary C Halloran
(2022)
KLC4 shapes axon arbors during development and mediates adult behavior
eLife 11:e74270.
https://doi.org/10.7554/eLife.74270

Share this article

https://doi.org/10.7554/eLife.74270

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

    1. Cell Biology
    2. Immunology and Inflammation
    Alejandro Rosell, Agata Adelajda Krygowska ... Esther Castellano Sanchez
    Research Article

    Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.