ArticleCell death and differentiation2026
Allele-specific CRISPR perturbation of the imprinted Dlk1-Dio3 domain reveals regulation of BMP-NOTCH-VEGF signaling in embryonic organogenesis.
Article in Cell death and differentiation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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