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<p>The <i>Dlk1–Dio3</i> imprinted domain is essential for mammalian development, yet its role in coordinating multi-organ embryogenesis is not fully understood. Here we generated four distinct mouse models via CRISPR/Cas9-mediated insertion of a transcriptional termination cassette within the <i>Dlk1–Dio3</i> domain, encompassing homozygous (HOMO), maternally inherited (MK), paternally inherited (PK), and wild-type alleles (WT), to elucidate parent-of-origin-specific effects. Integrative transcriptomic analyses across multiple scales revealed allele-specific dysregulation of imprinted genes and altered epigenetic stability at the locus. Crucially, scRNA-seq of embryonic day 14.5 (E14.5) liver, heart, and placenta showed that embryos homozygous or maternally targeted for <i>Dlk1–Dio3</i> inactivation arrest in development due to collapse of a BMP–NOTCH–VEGF signaling network. This manifests as organ-specific pathologies: (i) impaired decidual-trophoblast paracrine communication and aberrant BMP/WNT signaling compromise the maternal-fetal blood barrier, thereby disrupting placental angiogenesis and restricting maternal-fetal nutrient exchange; (ii) fetal liver hematopoietic progenitors display impaired myeloid lineage priming, concomitant with aberrant NOTCH and WNT signaling, leading to failure in hepatocyte differentiation; (iii) cardiac progenitors do not receive sufficient BMP–NOTCH–VEGF cues, yielding immature cardiomyocytes and vascular defects. Collectively, these findings identify the <i>Dlk1–Dio3</i> imprinted domain as a pivotal integrative hub for cell-type-specific signaling pathways during organogenesis and provide mechanistic insights into how dysregulation of genomic imprinting can precipitate systemic embryonic developmental failure.</p>

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Allele-specific CRISPR perturbation of the imprinted Dlk1–Dio3 domain reveals regulation of BMP–NOTCH–VEGF signaling in embryonic organogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Jie Xing,
  • Mengyan Zhang,
  • Haoran Yu,
  • Mu Su,
  • Ruiyang Zhai,
  • Hongli Wang,
  • Ji Li,
  • Qiong Wu,
  • Yan Zhang

摘要

The Dlk1–Dio3 imprinted domain is essential for mammalian development, yet its role in coordinating multi-organ embryogenesis is not fully understood. Here we generated four distinct mouse models via CRISPR/Cas9-mediated insertion of a transcriptional termination cassette within the Dlk1–Dio3 domain, encompassing homozygous (HOMO), maternally inherited (MK), paternally inherited (PK), and wild-type alleles (WT), to elucidate parent-of-origin-specific effects. Integrative transcriptomic analyses across multiple scales revealed allele-specific dysregulation of imprinted genes and altered epigenetic stability at the locus. Crucially, scRNA-seq of embryonic day 14.5 (E14.5) liver, heart, and placenta showed that embryos homozygous or maternally targeted for Dlk1–Dio3 inactivation arrest in development due to collapse of a BMP–NOTCH–VEGF signaling network. This manifests as organ-specific pathologies: (i) impaired decidual-trophoblast paracrine communication and aberrant BMP/WNT signaling compromise the maternal-fetal blood barrier, thereby disrupting placental angiogenesis and restricting maternal-fetal nutrient exchange; (ii) fetal liver hematopoietic progenitors display impaired myeloid lineage priming, concomitant with aberrant NOTCH and WNT signaling, leading to failure in hepatocyte differentiation; (iii) cardiac progenitors do not receive sufficient BMP–NOTCH–VEGF cues, yielding immature cardiomyocytes and vascular defects. Collectively, these findings identify the Dlk1–Dio3 imprinted domain as a pivotal integrative hub for cell-type-specific signaling pathways during organogenesis and provide mechanistic insights into how dysregulation of genomic imprinting can precipitate systemic embryonic developmental failure.