Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA, 90095, USA.
Eli and Edythe Broad Center for Regenerative Medicine, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Nat Commun. 2024 Aug 13;15(1):6948. doi: 10.1038/s41467-024-50780-5.
Cranial sutures separate neighboring skull bones and are sites of bone growth. A key question is how osteogenic activity is controlled to promote bone growth while preventing aberrant bone fusions during skull expansion. Using single-cell transcriptomics, lineage tracing, and mutant analysis in zebrafish, we uncover key developmental transitions regulating bone formation at sutures during skull expansion. In particular, we identify a subpopulation of mesenchyme cells in the mid-suture region that upregulate a suite of genes including BMP antagonists (e.g. grem1a) and pro-angiogenic factors. Lineage tracing with grem1a:nlsEOS reveals that this mid-suture subpopulation is largely non-osteogenic. Moreover, combinatorial mutation of BMP antagonists enriched in this mid-suture subpopulation results in increased BMP signaling in the suture, misregulated bone formation, and abnormal suture morphology. These data reveal establishment of a non-osteogenic mesenchyme population in the mid-suture region that restricts bone formation through local BMP antagonism, thus ensuring proper suture morphology.
颅缝分隔相邻的颅骨，并为骨骼生长提供场所。一个关键问题是如何控制成骨活性，以促进骨骼生长，同时防止颅骨扩张过程中的异常骨融合。通过在斑马鱼中使用单细胞转录组学、谱系追踪和突变分析，我们揭示了调节颅骨扩张过程中颅缝骨形成的关键发育转变。特别是，我们在中缝区域鉴定出一群间充质细胞，这些细胞上调了包括 BMP 拮抗剂（例如 grem1a）和促血管生成因子在内的一系列基因。利用 grem1a:nlsEOS 进行的谱系追踪表明，这个中缝亚群在很大程度上是非成骨的。此外，在这个中缝亚群中富集的 BMP 拮抗剂的组合突变导致在颅缝中 BMP 信号的增加、骨形成的失调和异常的颅缝形态。这些数据揭示了在中缝区域建立了一个非成骨的间充质细胞群体，通过局部 BMP 拮抗作用限制骨形成，从而确保适当的颅缝形态。
