Bobzin Lauren, Nickle Audrey, Ko Sebastian, Ince Michaela, Huang Aaron, Bhojwani Arshia, Roberts Ryan, Merrill Amy E
Center for Craniofacial Molecular Biology, Department of Biomedical Sciences, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
Development. 2025 Jan 15;152(2). doi: 10.1242/dev.204264. Epub 2025 Jan 20.
The calvarial bones of the infant skull are linked by transient fibrous joints known as sutures and fontanelles, which are essential for skull compression during birth and expansion during postnatal brain growth. Genetic conditions caused by pathogenic variants in FGFR2, such as Apert, Pfeiffer, and Crouzon syndromes, result in calvarial deformities due to premature suture fusion and a persistently open anterior fontanelle (AF). In this study, we investigated how Fgfr2 regulates AF closure by leveraging mouse genetics and single-cell transcriptomics. We find that AF cells, marked by the tendon/ligament factor SCX, are spatially organized into ecto- and endocranial domains that selectively differentiate into ligament, bone, and cartilage to form the posterior frontal suture. We show that AF cell differentiation is non-autonomously regulated by FGFR2 signaling in osteogenic front cells of the frontal bones, which regulate WNT signaling in neighboring AF cells by expressing the secreted WNT inhibitor Wif1. Upon loss of Fgfr2, Wif1 expression is downregulated, and AF cells fail to form the posterior frontal suture. This study identifies an FGF-WNT signaling circuit that that directs suture formation within the AF during postnatal development.
婴儿颅骨的颅盖骨通过称为缝和囟门的临时纤维关节相连，这些关节对于出生时颅骨的压缩和出生后大脑生长期间的扩张至关重要。由FGFR2中的致病变异引起的遗传疾病，如Apert、Pfeiffer和Crouzon综合征，会由于过早的缝融合和持续开放的前囟（AF）而导致颅盖骨畸形。在这项研究中，我们利用小鼠遗传学和单细胞转录组学研究了Fgfr2如何调节AF闭合。我们发现，以肌腱/韧带因子SCX为标记的AF细胞在空间上组织成颅外和颅内区域，这些区域选择性地分化为韧带、骨和软骨，以形成额后缝。我们表明，AF细胞的分化由额骨成骨前沿细胞中的FGFR2信号非自主调节，这些细胞通过表达分泌型WNT抑制剂Wif1来调节邻近AF细胞中的WNT信号。Fgfr2缺失后，Wif1表达下调，AF细胞无法形成额后缝。这项研究确定了一个FGF-WNT信号通路，该通路在出生后发育过程中指导AF内的缝形成。
