A Mir338-CDK8-mitochondrial axis governs lineage-specific osteogenesis and defines Runx2 pleiotropy in cranial sutures.

Authors

Hanshu Zhang, Xueying Ma, Junyan Peng, Qinhao Shen, Runze Jin, Yu Jia, Yu Zhou, Zhi Chen, Huan Liu

Published in

Journal of advanced research. Oct 11, 2026. Epub Oct 11, 2026.

Abstract

Developmental pattern formation critically depends on gene regulatory networks that enable context-dependent interpretation of molecular cues, yet how cells from distinct embryonic lineages in shared microenvironments produce divergent outcomes remains a central unresolved question. The murine skull provides a key model: the neural crest-derived posterior frontal (PF) suture fuses, while the mesoderm-derived sagittal (SAG) suture remains patent. A recently identified paradox exists: Runx2 haploinsufficiency impacts both sutures, but Mir338 cluster ablation selectively rescues the SAG suture, suggesting lineage-specific regulatory constraints.
This study aims to resolve this paradox by investigating how embryonic origin dictates osteoprogenitor responses to Runx2-Mir338 signaling.
We employed multi-omics (miRNA-seq, RNA-seq, scRNA-seq) and lineage tracing to define transcriptional heterogeneity, dissect Runx2 and Mir338-mediated lineage-specific regulation of osteoblastic subclusters, and identify differentially expressed mitochondrial-related genes and Cyclin-dependent kinase 8 (Cdk8). These findings were functionally validated through in vivo and in vitro assays.
We uncover that embryonic origin dictates osteoprogenitor responses to Runx2-Mir338 signaling through lineage-specific mitochondrial dynamics. In mesoderm-derived SAG sutures, Runx2 haploinsufficiency disrupts mitochondrial fragmentation, a process critical for ossification, via dysregulation of NADH: ubiquinone oxidoreductase subunit S5 (NDUFS5). We identify CDK8 as a novel direct target of Mir338 and a Runx2-activated gene that promotes mitochondrial fragmentation. This dual regulation of CDK8 establishes a dosage-sensitive "toggle switch" unique to SAG sutures, where restoring mitochondrial function via direct mitochondrial transplantation rescues ossification defects. In contrast, neural crest-derived PF sutures exhibit intrinsically low CDK8 expression, partially modulated by DNA methylation, rendering them unresponsive to Runx2-Mir338 modulation and mitochondrial rescue.
Our findings resolve the paradox of Runx2 pleiotropy by bridging positional identity, mitochondrial metabolism, and miRNA-mediated regulation, offering a redefined conceptual framework for understanding developmental processes and informing precision therapeutic strategies for congenital skeletal disorders.

PMID:
42860187
Bibliographic data and abstract were imported from PubMed on 12 Oct 2026.

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