Scholarlink

<p>Recurrent gain-of-function mutations in the histone reader protein ENL have been identified in Wilms tumor, the most prevalent pediatric kidney cancer. However, their pathological significance in kidney development and tumorigenesis in vivo remains elusive. Here, we generate mouse models mimicking ENL tumor (ENL<sup>T</sup>) mutations and show that heterozygous mutant expression in <i>Six2</i><sup>+</sup> nephrogenic or <i>Foxd1</i><sup>+</sup> stromal lineages leads to severe, lineage-specific kidney defects, both resulting in neonatal lethality. Six2-ENL<sup>T</sup> mutant kidneys display compromised cap mesenchyme, scant nephron tubules, and cystic glomeruli, indicative of premature progenitor commitment and blocked differentiation. Bulk and spatial transcriptomic analyses reveal aberrant activation of <i>Hox</i> and Wnt signaling genes in mutant nephrogenic cells. In contrast, Foxd1-ENL<sup>T</sup> mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, with dysregulated stromal gene expression affecting stroma-epithelium crosstalk. Our findings uncover distinct pathways through which ENL mutations disrupt nephrogenesis, providing a foundation for further investigations into their role in tumorigenesis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Expression of ENL YEATS domain tumor mutations in nephrogenic or stromal lineage impairs kidney development

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月14日

查看全文
  • Zhaoyu Xue,
  • Hongwen Xuan,
  • Kin Lau,
  • Yangzhou Su,
  • Marc Wegener,
  • Kuai Li,
  • Lisa Turner,
  • Marie Adams,
  • Xiaobing Shi,
  • Hong Wen

摘要

Recurrent gain-of-function mutations in the histone reader protein ENL have been identified in Wilms tumor, the most prevalent pediatric kidney cancer. However, their pathological significance in kidney development and tumorigenesis in vivo remains elusive. Here, we generate mouse models mimicking ENL tumor (ENLT) mutations and show that heterozygous mutant expression in Six2+ nephrogenic or Foxd1+ stromal lineages leads to severe, lineage-specific kidney defects, both resulting in neonatal lethality. Six2-ENLT mutant kidneys display compromised cap mesenchyme, scant nephron tubules, and cystic glomeruli, indicative of premature progenitor commitment and blocked differentiation. Bulk and spatial transcriptomic analyses reveal aberrant activation of Hox and Wnt signaling genes in mutant nephrogenic cells. In contrast, Foxd1-ENLT mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, with dysregulated stromal gene expression affecting stroma-epithelium crosstalk. Our findings uncover distinct pathways through which ENL mutations disrupt nephrogenesis, providing a foundation for further investigations into their role in tumorigenesis.