IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59346-5.html
   My bibliography  Save this article

METTL14 regulates chondrogenesis through the GDF5–RUNX–extracellular matrix gene axis during limb development

Author

Listed:
  • Nobuko Katoku-Kikyo

    (University of Minnesota
    University of Minnesota)

  • Hiroko Kawakami

    (University of Minnesota
    University of Minnesota)

  • Max Cantor

    (University of Minnesota
    University of Minnesota)

  • Yasuhiko Kawakami

    (University of Minnesota
    University of Minnesota)

  • Nobuaki Kikyo

    (University of Minnesota
    University of Minnesota)

Abstract

m6A RNA methylation is essential for many aspects of mammalian development but its roles in chondrogenesis remain largely unknown. Here, we show that m6A is necessary for chondrogenesis and limb morphogenesis using limb progenitor-specific knockout mice of Mettl14, an essential subunit in the m6A methyltransferase complex. The knockout disrupts cartilage anlagen formation in limb buds with 11 downregulated proteins known to dysregulate chondrogenesis and shorten limb skeletons upon mutation in mice and humans. Further studies show a gene regulatory hierarchy among the 11 proteins. m6A stabilizes the transcript and increases the protein level of GDF5, a BMP family member. This activates the chondrogenic transcription factor genes Runx2 and Runx3, whose mRNAs are also stabilized by m6A. They promote the transcription of six collagen genes and two other chondrogenic genes, Ddrgk1 and Pbxip1. Thus, this study uncovers an m6A-based cascade essential for chondrogenesis during limb skeletal development.

Suggested Citation

  • Nobuko Katoku-Kikyo & Hiroko Kawakami & Max Cantor & Yasuhiko Kawakami & Nobuaki Kikyo, 2025. "METTL14 regulates chondrogenesis through the GDF5–RUNX–extracellular matrix gene axis during limb development," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59346-5
    DOI: 10.1038/s41467-025-59346-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59346-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-59346-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Yunshu Wu & Liang Xie & Mengyuan Wang & Qiuchan Xiong & Yuchen Guo & Yu Liang & Jing Li & Rui Sheng & Peng Deng & Yuan Wang & Rixin Zheng & Yizhou Jiang & Ling Ye & Qianming Chen & Xuedong Zhou & Shui, 2018. "Mettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    2. Quanbo Ji & Xiaojie Xu & Lei Kang & Yameng Xu & Jingbo Xiao & Stuart B. Goodman & Xiang Zhu & Wenchao Li & Juan Liu & Xu Gao & Zhifeng Yan & Yuxuan Zheng & Zheng Wang & William J. Maloney & Qinong Ye , 2019. "Hematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    3. Peng He & Brian A. Williams & Diane Trout & Georgi K. Marinov & Henry Amrhein & Libera Berghella & Say-Tar Goh & Ingrid Plajzer-Frick & Veena Afzal & Len A. Pennacchio & Diane E. Dickel & Axel Visel &, 2020. "The changing mouse embryo transcriptome at whole tissue and single-cell resolution," Nature, Nature, vol. 583(7818), pages 760-767, July.
    4. Yuki Matsushita & Angel Ka Yan Chu & Chiaki Tsutsumi-Arai & Shion Orikasa & Mizuki Nagata & Sunny Y. Wong & Joshua D. Welch & Wanida Ono & Noriaki Ono, 2022. "The fate of early perichondrial cells in developing bones," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Rachel K. Lex & Weiqiang Zhou & Zhicheng Ji & Kristin N. Falkenstein & Kaleigh E. Schuler & Kathryn E. Windsor & Joseph D. Kim & Hongkai Ji & Steven A. Vokes, 2022. "GLI transcriptional repression is inert prior to Hedgehog pathway activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Martin Arostegui & R. Wilder Scott & Kerstin Böse & T. Michael Underhill, 2022. "Cellular taxonomy of Hic1+ mesenchymal progenitor derivatives in the limb: from embryo to adult," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    3. Dongsheng Mao & Xiaochen Tang & Runchi Zhang & Song Hu & Hongquan Gou & Penghui Zhang & Wenxing Li & Qiuhui Pan & Bing Shen & Xiaoli Zhu, 2025. "Multichrome encoding-based multiplexed, spatially resolved imaging reveals single-cell RNA epigenetic modifications heterogeneity," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    4. Michael J. Geuenich & Dae-won Gong & Kieran R. Campbell, 2024. "The impacts of active and self-supervised learning on efficient annotation of single-cell expression data," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Lindsey R. Conroy & Harrison A. Clarke & Derek B. Allison & Samuel Santos Valenca & Qi Sun & Tara R. Hawkinson & Lyndsay E. A. Young & Juanita E. Ferreira & Autumn V. Hammonds & Jaclyn B. Dunne & Robe, 2023. "Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Wanying Wu & Jinyang Zhang & Xiaofei Cao & Zhengyi Cai & Fangqing Zhao, 2022. "Exploring the cellular landscape of circular RNAs using full-length single-cell RNA sequencing," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Caojie Liu & Qiuchan Xiong & Qiwen Li & Weimin Lin & Shuang Jiang & Danting Zhang & Yuan Wang & Xiaobo Duan & Ping Gong & Ning Kang, 2022. "CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Angela Tung & Megan M. Sperry & Wesley Clawson & Ananya Pavuluri & Sydney Bulatao & Michelle Yue & Ramses Martinez Flores & Vaibhav P. Pai & Patrick McMillen & Franz Kuchling & Michael Levin, 2024. "Embryos assist morphogenesis of others through calcium and ATP signaling mechanisms in collective teratogen resistance," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    9. Donghyun Kang & Jeeyeon Lee & Jisu Jung & Bradley A. Carlson & Moon Jong Chang & Chong Bum Chang & Seung-Baik Kang & Byung Cheon Lee & Vadim N. Gladyshev & Dolph L. Hatfield & Byeong Jae Lee & Jin-Hon, 2022. "Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    10. Yang Zhao & Jingyuan Ning & Hongqi Teng & Yalan Deng & Marisela Sheldon & Lei Shi & Consuelo Martinez & Jie Zhang & Annie Tian & Yutong Sun & Shinichi Nakagawa & Fan Yao & Hai Wang & Li Ma, 2024. "Long noncoding RNA Malat1 protects against osteoporosis and bone metastasis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59346-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.