Center for Craniofacial Innovation, Children's Hospital of Philadelphia Research, Institute, Children's Hospital of Philadelphia, Philadelphia, United States.
Division of Plastic and Reconstructive Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States.
Elife. 2024 Nov 21;13:RP91648. doi: 10.7554/eLife.91648.
Wnt signaling plays crucial roles in embryonic patterning including the regulation of convergent extension (CE) during gastrulation, the establishment of the dorsal axis, and later, craniofacial morphogenesis. Further, Wnt signaling is a crucial regulator of craniofacial morphogenesis. The adapter proteins Dact1 and Dact2 modulate the Wnt signaling pathway through binding to Disheveled. However, the distinct relative functions of Dact1 and Dact2 during embryogenesis remain unclear. We found that and genes have dynamic spatiotemporal expression domains that are reciprocal to one another suggesting distinct functions during zebrafish embryogenesis. Both and contribute to axis extension, with compound mutants exhibiting a similar CE defect and craniofacial phenotype to the mutant. Utilizing single-cell RNAseq and an established noncanonical Wnt pathway mutant with a shortened axis (), we identified -specific roles during early development. Comparative whole transcriptome analysis between wildtype and and wildtype and compound mutants revealed a novel role for in regulating the mRNA expression of the classical calpain . Overexpression of phenocopies craniofacial dysmorphology. These results identify a previously unappreciated role of and calcium-dependent proteolysis during embryogenesis. Taken together, our findings highlight the distinct and overlapping roles of and in embryonic craniofacial development, providing new insights into the multifaceted regulation of Wnt signaling.
Wnt 信号通路在胚胎形态发生中发挥着至关重要的作用,包括在原肠胚形成过程中调节会聚延伸 (CE)、建立背轴以及随后的颅面形态发生。此外,Wnt 信号通路还是颅面形态发生的关键调节因子。衔接蛋白 Dact1 和 Dact2 通过与 Disheveled 结合来调节 Wnt 信号通路。然而,Dact1 和 Dact2 在胚胎发生过程中的不同相对功能仍不清楚。我们发现,和 基因具有动态的时空表达域,彼此互为反转,表明在斑马鱼胚胎发生过程中有不同的功能。和 都有助于轴的延伸,复合突变体表现出与 突变体相似的 CE 缺陷和颅面表型。利用单细胞 RNAseq 和一个具有缩短轴的已建立的非经典 Wnt 途径突变体 (),我们在早期发育中鉴定了 -特异性作用。野生型和 以及野生型和 复合突变体之间的全转录组比较分析揭示了 在调节经典钙蛋白酶 mRNA 表达中的新作用。过表达 可模拟 颅面畸形。这些结果确定了 在胚胎发生过程中钙依赖性蛋白水解作用的以前未被认识到的作用。总之,我们的研究结果突出了 和 在胚胎颅面发育中的独特和重叠作用,为 Wnt 信号通路的多方面调节提供了新的见解。
Nucleosides Nucleotides Nucleic Acids. 2024
Cell Mol Life Sci. 2022-11-12
Innovation (Camb). 2021-7-1
Front Cell Dev Biol. 2021-8-16
Cell. 2021-6-24
Development. 2020-12-23
Front Endocrinol (Lausanne). 2020