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<p>m<sup>6</sup>A RNA methylation is essential for many aspects of mammalian development but its roles in chondrogenesis remain largely unknown. Here, we show that m<sup>6</sup>A is necessary for chondrogenesis and limb morphogenesis using limb progenitor-specific knockout mice of <i>Mettl14</i>, an essential subunit in the m<sup>6</sup>A 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. m<sup>6</sup>A stabilizes the transcript and increases the protein level of GDF5, a BMP family member. This activates the chondrogenic transcription factor genes <i>Runx2</i> and <i>Runx3</i>, whose mRNAs are also stabilized by m<sup>6</sup>A. They promote the transcription of six collagen genes and two other chondrogenic genes, <i>Ddrgk1</i> and <i>Pbxip1</i>. Thus, this study uncovers an m<sup>6</sup>A-based cascade essential for chondrogenesis during limb skeletal development.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月30日

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  • Nobuko Katoku-Kikyo,
  • Hiroko Kawakami,
  • Max Cantor,
  • Yasuhiko Kawakami,
  • Nobuaki Kikyo

摘要

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.