空间多组学揭示了 Wnt 调制器 Dkk2 在腭裂发生过程中的作用"。

J O Piña, R Raju, D M Roth, E W Winchester, C Padilla, J Iben, F R Faucz, J L Cotney, R N D'Souza
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引用次数: 0

摘要

腭裂是颅面综合征中最常见的遗传性疾病,多种遗传和环境病因是腭裂的发病机理。目前对胚胎发育过程中调控腭骨分化和模式化的分子机制的了解还很有限,需要开发创新的诊断和治疗方法。本研究使用具有一致继发性腭裂表型的 Pax9-/- 小鼠模型来研究 Pax9 在腭骨生成过程中的作用。虽然之前的研究发现了Pax9-/-腭间质中Wnt通路调节剂Dkk1和Dkk2的上调,但空间分辨率和技术的限制限制了更有力的分析。在这里,通过原位高度多重靶向单细胞空间谱分析技术验证的单核转录组学和染色质可及性测定的数据表明,Pax9+和成骨细胞群之间存在不同的关系。缺失 Pax9 会导致空间受限的成骨域,该域以 Dkk2 为界,而 Dkk2 通常与间充质中的 Pax9 相互连接。此外,Pax9的缺失还导致腭骨成骨间充质细胞的正常成骨分化过程中断。这些结果表明,依赖于Pax9的Wnt信号调节器会影响腭形成过程中的成骨编程,从而可能导致观察到的腭裂表型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Spatial Multi-omics Reveals the Role of the Wnt Modulator, Dkk2, in Palatogenesis'.

Multiple genetic and environmental etiologies contribute to the pathogenesis of cleft palate, which is the most common of the inherited disorders of the craniofacial complex. Insights into the molecular mechanisms regulating osteogenic differentiation and patterning in the palate during embryogenesis are limited and needed for the development of innovative diagnostics and cures. This study used the Pax9-/- mouse model with a consistent phenotype of cleft secondary palate to investigate the role of Pax9 in the process of palatal osteogenesis. Although prior research has identified the upregulation of Wnt pathway modulators Dkk1 and Dkk2 in Pax9-/- palate mesenchyme, limitations of spatial resolution and technology restricted a more robust analysis. Here, data from single-nucleus transcriptomics and chromatin accessibility assays validated by in situ highly multiplex targeted single-cell spatial profiling technology suggest a distinct relationship between Pax9+ and osteogenic populations. Loss of Pax9 results in spatially restricted osteogenic domains bounded by Dkk2, which normally interfaces with Pax9 in the mesenchyme. Moreover, the loss of Pax9 leads to a disruption in the normal osteodifferentiaion of palatal osteogenic mesenchymal cells. These results suggest that Pax9-dependent Wnt signaling modulators influence osteogenic programming during palate formation, potentially contributing to the observed cleft palate phenotype.

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