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

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.

Reviewing Editor

  1. Xu Cao, Johns Hopkins University, United States

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.

Version 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

  • 714
    views
  • 116
    downloads
  • 2
    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. 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

Share this article

https://doi.org/10.7554/eLife.80013

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Jiabin Pan, Rui Zhou ... Xiang-dong Li
    Research Article

    Transport and localization of melanosome at the periphery region of melanocyte are depended on myosin-5a (Myo5a), which associates with melanosome by interacting with its adaptor protein melanophilin (Mlph). Mlph contains four functional regions, including Rab27a-binding domain, Myo5a GTD-binding motif (GTBM), Myo5a exon F-binding domain (EFBD), and actin-binding domain (ABD). The association of Myo5a with Mlph is known to be mediated by two specific interactions: the interaction between the exon-F-encoded region of Myo5a and Mlph-EFBD and that between Myo5a-GTD and Mlph-GTBM. Here, we identify a third interaction between Myo5a and Mlph, that is, the interaction between the exon-G-encoded region of Myo5a and Mlph-ABD. The exon-G/ABD interaction is independent from the exon-F/EFBD interaction and is required for the association of Myo5a with melanosome. Moreover, we demonstrate that Mlph-ABD interacts with either the exon-G or actin filament, but cannot interact with both of them simultaneously. Based on above findings, we propose a new model for the Mlph-mediated Myo5a transportation of melanosomes.

    1. Cell Biology
    Yuhao Wang, Linhao Ruan ... Rong Li
    Research Article

    Mitochondria are the cellular energy hub and central target of metabolic regulation. Mitochondria also facilitate proteostasis through pathways such as the ‘mitochondria as guardian in cytosol’ (MAGIC) whereby cytosolic misfolded proteins (MPs) are imported into and degraded inside mitochondria. In this study, a genome-wide screen in Saccharomyces cerevisiae uncovered that Snf1, the yeast AMP-activated protein kinase (AMPK), inhibits the import of MPs into mitochondria while promoting mitochondrial biogenesis under glucose starvation. We show that this inhibition requires a downstream transcription factor regulating mitochondrial gene expression and is likely to be conferred through substrate competition and mitochondrial import channel selectivity. We further show that Snf1/AMPK activation protects mitochondrial fitness in yeast and human cells under stress induced by MPs such as those associated with neurodegenerative diseases.