A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis
- Northwestern University Feinberg School of Medicine, United States
Abstract
The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated UBQLN4 variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a UBQLN4 substrate. Inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways.
Article and author information
Author details
Yongchao Charles Ma
Funding
National Institute of Neurological Disorders and Stroke (NS094564)
- Yongchao Charles Ma
National Institute on Aging (AG043970)
- Yongchao Charles Ma
Hartwell Foundation
- Yongchao Charles Ma
Whitehall Foundation
- Yongchao Charles Ma
National Institute of Neurological Disorders and Stroke (NS078504)
- Teepu Siddique
Les Turner ALS Foundation
- Teepu Siddique
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal use in this study has been approved by the Institutional Animal Care and Use Committee (IACUC) of the Lurie Children's Hospital of Chicago (protocols 14-012 and 15-006). All studies were conducted in accordance with the US Public Health Service's Policy on Humane Care and Use of Laboratory Animals.
Human subjects: The use of human subjects in this study has been approved by the Northwestern University Institutional Review Board (IRB). Informed consent was obtained from all subjects.
Copyright
© 2017, Edens 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
-
- 5,136
- views
-
- 704
- downloads
-
- 35
- 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)
A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis
eLife 6:e25453.
https://doi.org/10.7554/eLife.25453
Further reading
-
- Cell Biology
The accumulation of SIRT4 in the nuclei of kidney cells drives kidney fibrosis, so blocking the movement of this protein could be a potential therapeutic strategy against fibrosis.
-
- Cell Biology
- Developmental Biology
Chondrocyte columns, which are a hallmark of growth plate architecture, play a central role in bone elongation. Columns are formed by clonal expansion following rotation of the division plane, resulting in a stack of cells oriented parallel to the growth direction. In this work, we analyzed hundreds of Confetti multicolor clones in growth plates of mouse embryos using a pipeline comprising 3D imaging and algorithms for morphometric analysis. Surprisingly, analysis of the elevation angles between neighboring pairs of cells revealed that most cells did not display the typical stacking pattern associated with column formation, implying incomplete rotation of the division plane. Morphological analysis revealed that although embryonic clones were elongated, they formed clusters oriented perpendicular to the growth direction. Analysis of growth plates of postnatal mice revealed both complex columns, composed of ordered and disordered cell stacks, and small, disorganized clusters located in the outer edges. Finally, correlation between the temporal dynamics of the ratios between clusters and columns and between bone elongation and expansion suggests that clusters may promote expansion, whereas columns support elongation. Overall, our findings support the idea that modulations of division plane rotation of proliferating chondrocytes determines the formation of either clusters or columns, a multifunctional design that regulates morphogenesis throughout pre- and postnatal bone growth. Broadly, this work provides a new understanding of the cellular mechanisms underlying growth plate activity and bone elongation during development.
