小鼠颅神经嵴细胞中成纤维细胞生长因子-9信号增强诱发腭裂。

Stem cells and development Pub Date : 2024-10-01 Epub Date: 2024-08-22 DOI:10.1089/scd.2024.0077
Chensheng Lin, Shiyu Liu, Ningsheng Ruan, Jiang Chen, YiPing Chen, Yanding Zhang, Jian Zhang
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引用次数: 0

摘要

尽管成纤维细胞生长因子(FGF)信号传导增强已被证实在许多由人类舌位不正引起的综合征腭裂病例中起着关键作用,但能再现这种表型的动物模型却很有限,其确切的机制仍难以捉摸。已发现 FGF9 基因突变具有功能缺失或功能增益效应,与人类腭裂有关。在这里,我们用特异性激活颅神经嵴细胞(CNCCs)的转基因 Fgf9 等位基因生成了一个小鼠模型,旨在阐明 Fgf9 在腭裂发生过程中的功能增益效应。我们观察到突变小鼠腭裂的穿透率为 100%。进一步的分析表明,腭骨架的形态发生能力没有固有缺陷,但被动抬高的舌头阻碍了腭骨架的抬高,导致了腭裂。这种舌错位是由颞下颌关节(TMJ)发育不良造成的后部空间限制诱发的,其特点是髁突内Sox9+祖细胞减少和下颌骨后部结构性尺寸减小。我们的研究结果突显了过多的 FGF 信号在破坏腭发育过程中的空间协调性中的关键作用,并表明腭骨架抬高与早期颞下颌关节发育之间存在潜在联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cleft Palate Induced by Augmented Fibroblast Growth Factor-9 Signaling in Cranial Neural Crest Cells in Mice.

Although enhanced fibroblast growth factor (FGF) signaling has been demonstrated to be crucial in many cases of syndromic cleft palate caused by tongue malposition in humans, animal models that recapitulate this phenotype are limited, and the precise mechanisms remain elusive. Mutations in FGF9 with the effect of either loss- or gain-of-function effects have been identified to be associated with cleft palate in humans. Here, we generated a mouse model with a transgenic Fgf9 allele specifically activated in cranial neural crest cells, aiming to elucidate the gain-of-function effects of Fgf9 in palatogenesis. We observed cleft palate with 100% penetrance in mutant mice. Further analysis demonstrated that no inherent defects in the morphogenic competence of palatal shelves could be found, but a passively lifted tongue prevented the elevation of palatal shelves, leading to the cleft palate. This tongue malposition was induced by posterior spatial confinement that was exerted by temporomandibular joint (TMJ) dysplasia characterized by a reduction in Sox9+ progenitors within the condyle and a structural decrease in the posterior dimension of the lower jaw. Our findings highlight the critical role of excessive FGF signaling in disrupting spatial coordination during palate development and suggest a potential association between palatal shelf elevation and early TMJ development.

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