1. Cell Biology

Specific deletion of Axin1 leads to activation of β-catenin/BMP signaling resulting in fibular hemimelia phenotype in mice

  1. Rong Xie
  2. Dan Yi
  3. Daofu Zeng
  4. Qiang Jie
  5. Qinglin Kang
  6. Zeng Zhang
  7. Zhenlin Zhang
  8. Guozhi Xiao
  9. Lin Chen
  10. Liping Tong  Is a corresponding author
  11. Di Chen  Is a corresponding author
  1. Rush University Medical Center, United States
  2. Chinese Academy of Sciences, China
  3. Xi'an Jiaotong University, China
  4. Shanghai JiaoTong University, China
  5. Southern University of Science and Technology, China
  6. Army Medical University, China
https://doi.org/10.7554/eLife.80013
Share this article
Cite this article
  1. Rong Xie
  2. Dan Yi
  3. Daofu Zeng
  4. Qiang Jie
  5. Qinglin Kang
  6. Zeng Zhang
  7. Zhenlin Zhang
  8. Guozhi Xiao
  9. Lin Chen
  10. Liping Tong
  11. Di Chen
(2022)
Specific deletion of Axin1 leads to activation of β-catenin/BMP signaling resulting in fibular hemimelia phenotype in mice
eLife 11:e80013.
https://doi.org/10.7554/eLife.80013
  2. Download BibTeX
  3. Download .RIS

Abstract

Axin1 is a key regulator of canonical Wnt signaling pathway. Roles of Axin1 in skeletal development and in disease occurrence have not been fully defined. Here, we report that Axin1 is essential for lower limb development. Specific deletion of Axin1 in limb mesenchymal cells leads to fibular hemimelia (FH)-like phenotype, associated with tarsal coalition. Further studies demonstrate that FH disease is associated with additional defects in Axin1 knockout (KO) mice, including decreased osteoclast formation and defects in angiogenesis. We then provide in vivo evidence showing that Axin1 controls limb development through both canonical β-catenin and BMP signaling pathways. We demonstrate that inhibition of β-catenin or BMP signaling could significantly reverse the FH phenotype in mice. Together, our findings reveal that integration of β-catenin and BMP signaling by Axin1 is required for lower limb development. Defect in Axin1 signaling could lead to the development of FH disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures.

Article and author information

Author details

  1. Rong Xie

    Department of Orthopedic Surgery, Rush University Medical Center, Chicago, United States
    Competing interests
    No competing interests declared.

  2. Dan Yi

    Research Center for Computer-aided Drug Discovery, Chinese Academy of Sciences, Shenzhen, China
    Competing interests
    No competing interests declared.

  3. Daofu Zeng

    Research Center for Computer-aided Drug Discovery, Chinese Academy of Sciences, Shenzhen, China
    Competing interests
    No competing interests declared.

  4. Qiang Jie

    Department of Orthopedic Surgery, Xi'an Jiaotong University, Xi'an, China
    Competing interests
    No competing interests declared.

  5. Qinglin Kang

    Department of Orthopedic Surgery, Shanghai JiaoTong University, Shanghai, China
    Competing interests
    No competing interests declared.

  6. Zeng Zhang

    Department of Orthopedic Surgery, Shanghai JiaoTong University, Shanghai, China
    Competing interests
    No competing interests declared.

  7. Zhenlin Zhang

    Department of Osteoporosis and Bone Diseases, Shanghai JiaoTong University, Shanghai, China
    Competing interests
    No competing interests declared.

  8. Guozhi Xiao

    Southern University of Science and Technology, Shenzhen, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4269-2450

  9. Lin Chen

    Department of Wound Repair and Rehabilitation, Army Medical University, Chongqing, China
    Competing interests
    No competing interests declared.

  10. Liping Tong

    Research Center for Computer-aided Drug Discovery, Chinese Academy of Sciences, Shenzhen, China
    For correspondence
    lp.tong@siat.ac.cn
    Competing interests
    No competing interests declared.

  11. Di Chen

    Research Center for Computer-aided Drug Discovery, Chinese Academy of Sciences, Shenzhen, China
    For correspondence
    di.chen@siat.ac.cn
    Competing interests
    Di Chen, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4258-3457

Funding

National Natural Science Foundation of China (82030067)

  • Di Chen

National Natural Science Foundation of China (82161160342)

  • Di Chen

National Natural Science Foundation of China (82172397)

  • Liping Tong

National Natural Science Foundation of China (81974320)

  • Zhenlin Zhang

National Key Research and Development Program of China (2021YFB3800800)

  • Di Chen

National Key Research and Development Program of China (2021YFB3800800)

  • Liping Tong

Guangdong Basic and Applied Basic Research Foundation (2021A1515111075)

  • Dan Yi

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 strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (SIAT-IACUC-200302-YYS-CD-A1063) of the Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences.

Reviewing Editor

  1. Xu Cao, Johns Hopkins University, United States

Publication history

  1. Received: May 5, 2022
  2. Preprint posted: July 5, 2022 (view preprint)
  3. Accepted: December 20, 2022
  4. Accepted Manuscript published: December 21, 2022 (version 1)
  5. Version of Record published: January 5, 2023 (version 2)

Copyright

© 2022, Xie 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

  • 318
    Page views
  • 70
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Rong Xie
  2. Dan Yi
  3. Daofu Zeng
  4. Qiang Jie
  5. Qinglin Kang
  6. Zeng Zhang
  7. Zhenlin Zhang
  8. Guozhi Xiao
  9. Lin Chen
  10. Liping Tong
  11. Di Chen
(2022)
Specific deletion of Axin1 leads to activation of β-catenin/BMP signaling resulting in fibular hemimelia phenotype in mice
eLife 11:e80013.
https://doi.org/10.7554/eLife.80013

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Nuclear SUN1 stabilizes endothelial cell junctions via microtubules to regulate blood vessel formation

    Danielle B Buglak, Pauline Bougaran ... Victoria L Bautch
    Research Article

    Endothelial cells line all blood vessels, where they coordinate blood vessel formation and the blood-tissue barrier via regulation of cell-cell junctions. The nucleus also regulates endothelial cell behaviors, but it is unclear how the nucleus contributes to endothelial cell activities at the cell periphery. Here, we show that the nuclear-localized linker of the nucleoskeleton and cytoskeleton (LINC) complex protein SUN1 regulates vascular sprouting and endothelial cell-cell junction morphology and function. Loss of murine endothelial Sun1 impaired blood vessel formation and destabilized junctions, angiogenic sprouts formed but retracted in SUN1-depleted sprouts, and zebrafish vessels lacking Sun1b had aberrant junctions and defective cell-cell connections. At the cellular level, SUN1 stabilized endothelial cell-cell junctions, promoted junction function, and regulated contractility. Mechanistically, SUN1 depletion altered cell behaviors via the cytoskeleton without changing transcriptional profiles. Reduced peripheral microtubule density, fewer junction contacts, and increased catastrophes accompanied SUN1 loss, and microtubule depolymerization phenocopied effects on junctions. Depletion of GEF-H1, a microtubule-regulated Rho activator, or the LINC complex protein nesprin-1 rescued defective junctions of SUN1-depleted endothelial cells. Thus, endothelial SUN1 regulates peripheral cell-cell junctions from the nucleus via LINC complex-based microtubule interactions that affect peripheral microtubule dynamics and Rho-regulated contractility, and this long-range regulation is important for proper blood vessel sprouting and junction integrity.

    1. Cell Biology

    Defects in lipid homeostasis reflect the function of TANGO2 in phospholipid and neutral lipid metabolism

    Agustin Leonardo Lujan, Ombretta Foresti ... Vivek Malhotra
    Research Article Updated

    We show that TANGO2 in mammalian cells localizes predominantly to mitochondria and partially at mitochondria sites juxtaposed to lipid droplets (LDs) and the endoplasmic reticulum. HepG2 cells and fibroblasts of patients lacking TANGO2 exhibit enlarged LDs. Quantitative lipidomics revealed a marked increase in lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes were exacerbated in nutrient-starved cells. Based on our data, we suggest that TANGO2 function is linked to acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. The defect in acyl-CoA availability impacts the metabolism of many other fatty acids, generates high levels of reactive oxygen species, and promotes lipid peroxidation. We suggest that the increased size of LDs is a combination of enrichment in peroxidized lipids and a defect in their catabolism. Our findings help explain the physiological consequence of mutations in TANGO2 that induce acute metabolic crises, including rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, often leading to fatality upon starvation and stress.

    1. Cell Biology
    2. Cancer Biology

    Transferred mitochondria accumulate reactive oxygen species, promoting proliferation

    Chelsea U Kidwell, Joseph R Casalini ... Minna Roh-Johnson
    Research Article Updated

    Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.