METTL3通过刺猬调节支持颅骨生成的Ctsk+系谱

Journal of dental research Pub Date : 2024-07-01 Epub Date: 2024-05-16 DOI:10.1177/00220345241245033
R Xu, R Sheng, W Lin, S Jiang, D Zhang, L Liu, K Lei, X Li, Z Liu, X Zhang, Y Wang, D Seriwatanachai, X Zhou, Q Yuan
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摘要

N6-甲基腺苷(m6A)修饰是由甲基转移酶样3(METTL3)催化的真核信使RNA修饰,在干细胞命运决定中起着关键作用。颅骨的发育和维持由颅缝协调。Cathepsin K(CTSK)阳性的钙质干细胞(CSCs)有助于小鼠钙质骨化。然而,m6A修饰在调控钙骨发育过程中Ctsk+系细胞的作用仍不明确。在这里,我们发现 METTL3 与颅骨非骨形成的 Ctsk+ 系细胞共定位,这些细胞也与 GLI1 的表达有关。在新生儿发育过程中,Ctsk+系细胞中的Mettl3缺失会延迟缝合线的形成并降低矿化度。在成年期的维持过程中,Ctsk+系细胞中Mettl3的缺失会影响犊骨的形成,其特点是骨孔隙率增加、骨髓腔增大、骨细胞数量减少且细胞轮廓不发达。甲基化 RNA 免疫沉淀测序和 RNA 测序数据的分析表明,METTL3 的缺失减少了 Hedgehog(Hh)信号通路。通过杂交 Sufufl/+ 等位基因或局部注射 SAG21 恢复 Hh 信号通路可部分缓解异常。我们的数据表明,METTL3通过调节Hh信号通路来调节支持钙骨形成的Ctsk+系细胞,为临床治疗颅顶骨疾病提供了新的思路。
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METTL3 Modulates Ctsk+ Lineage Supporting Cranial Osteogenesis via Hedgehog.

N6-methyladenosine (m6A) modification, a eukaryotic messenger RNA modification catalyzed by methyltransferase-like 3 (METTL3), plays a pivotal role in stem cell fate determination. Calvarial bone development and maintenance are orchestrated by the cranial sutures. Cathepsin K (CTSK)-positive calvarial stem cells (CSCs) contribute to mice calvarial ossification. However, the role of m6A modification in regulating Ctsk+ lineage cells during calvarial development remains elusive. Here, we showed that METTL3 was colocalized with cranial nonosteoclastic Ctsk+ lineage cells, which were also associated with GLI1 expression. During neonatal development, depletion of Mettl3 in the Ctsk+ lineage cells delayed suture formation and decreased mineralization. During adulthood maintenance, loss of Mettl3 in the Ctsk+ lineage cells impaired calvarial bone formation, which was featured by the increased bone porosity, enhanced bone marrow cavity, and decreased number of osteocytes with the less-developed cellular outline. The analysis of methylated RNA immunoprecipitation sequencing and RNA sequencing data indicated that loss of METTL3 reduced Hedgehog (Hh) signaling pathway. Restoration of Hh signaling pathway by crossing Sufufl/+ alleles or by local administration of SAG21 partially rescued the abnormity. Our data indicate that METTL3 modulates Ctsk+ lineage cells supporting calvarial bone formation by regulating the Hh signaling pathway, providing new insights for clinical treatment of skull vault osseous diseases.

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