Apical expansion of calvarial osteoblasts and suture patency is dependent on graded fibronectin cues.
Apical expansion of calvarial osteoblasts and suture patency is dependent on graded fibronectin cues.
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颅骨成骨细胞的顶端扩张和缝线通畅取决于分级的纤连蛋白线索。
DOI：
10.1101/2023.01.16.524278
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Atit,RadhikaP
中科院分区：
文献类型：
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作者：
Feng,Xiaotian;Molteni,Helen;Gregory,Megan;Lanza,Jennifer;Polsani,Nikaya;Wyetzner,Rachel;Hawkins,MBrent;Holmes,Greg;Hopyan,Sevan;Harris,MatthewP;Atit,RadhikaP
颅顶或颅骨由互锁的骨板组成。颅缝过早融合（颅缝早闭，CS）或持续性囟门是颅骨发育的常见缺陷。尽管这些疾病的一些遗传原因是已知的，但我们对指导这些骨骼祖细胞生长和迁移的指令缺乏了解，这可能会影响缝合线的通畅。在这里，我们确定了在颅骨成骨细胞顶端扩张之前小鼠胚胎颅间充质（CM）中纤连蛋白（FN1）蛋白的分级表达。 CS 的综合征形式表现出 FN1 表达失调，我们发现 FN1 表达在小鼠 CS 模型中也发生了改变。 CM 中 Fn1 的条件性缺失会通过改变细胞极性和形状而导致额骨扩张减少。为了解决骨祖细胞如何与观察到的 FN1 预模式相互作用，我们有条件地消融 Wasl/N-Wasp 以破坏迁移细胞中的 F-肌动蛋白连接，影响片状伪足和细胞基质相互作用。神经嵴靶向删除 Wasl 会导致肌动蛋白网络减少，额骨原基扩张减少，与条件性 Fn1 突变体类似。有趣的是，Fn1 和 Wasl 突变体中的颅盖形成缺陷，在增殖、存活或成骨方面没有显着变化。最后，我们发现 CM 限制性 Fn1 缺失导致冠状缝过早融合。这些数据支持 FN1 作为颅骨成骨细胞迁移的定向基质的模型，这可能是不同遗传病因的许多颅骨疾病的常见机制。
The skull roof, or calvaria, is comprised of interlocking plates of bone. Premature suture fusion (craniosynostosis, CS) or persistent fontanelles are common defects in calvarial development. Although some of the genetic causes of these disorders are known, we lack an understanding of the instructions directing the growth and migration of progenitors of these bones, which may affect the suture patency. Here, we identify graded expression of Fibronectin (FN1) protein in the mouse embryonic cranial mesenchyme (CM) that precedes the apical expansion of calvarial osteoblasts. Syndromic forms of CS exhibit dysregulated FN1 expression, and we find FN1 expression is altered in a mouse CS model as well. Conditional deletion of Fn1 in CM causes diminished frontal bone expansion by altering cell polarity and shape. To address how osteoprogenitors interact with the observed FN1 prepattern, we conditionally ablate Wasl/N-Wasp to disrupt F-actin junctions in migrating cells, impacting lamellipodia and cell-matrix interaction. Neural crest-targeted deletion of Wasl results in a diminished actin network and reduced expansion of frontal bone primordia similar to conditional Fn1 mutants. Interestingly, defective calvaria formation in both the Fn1 and Wasl mutants occurs without a significant change in proliferation, survival, or osteogenesis. Finally, we find that CM-restricted Fn1 deletion leads to premature fusion of coronal sutures. These data support a model of FN1 as a directional substrate for calvarial osteoblast migration that may be a common mechanism underlying many cranial disorders of disparate genetic etiologies.