Marchini Marta, Hu Diane, Lo Vercio Lucas, Young Nathan M, Forkert Nils D, Hallgrímsson Benedikt, Marcucio Ralph
Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada.
McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, AB, Canada.
Front Cell Dev Biol. 2021 Mar 29;9:644099. doi: 10.3389/fcell.2021.644099. eCollection 2021.
Canonical Wnt signaling plays multiple roles critical to normal craniofacial development while its dysregulation is known to be involved in structural birth defects of the face. However, when and how Wnt signaling influences phenotypic variation, including those associated with disease, remains unclear. One potential mechanism is via Wnt signaling's role in the patterning of an early facial signaling center, the frontonasal ectodermal zone (FEZ), and its subsequent regulation of early facial morphogenesis. For example, Wnt signaling may directly alter the shape and/or magnitude of expression of the () domain in the FEZ. To test this idea, we used a replication-competent avian sarcoma retrovirus (RCAS) encoding to modulate its expression in the facial mesenchyme. We then quantified and compared ontogenetic changes in treated to untreated embryos in the three-dimensional (3D) shape of both the expression domain of the FEZ, and the morphology of the facial primordia and brain using iodine-contrast microcomputed tomography imaging and 3D geometric morphometrics (3DGM). We found that increased expression in early stages of head development produces correlated variation in shape between both structural and signaling levels of analysis. In addition, altered activation disrupted the integration between the forebrain and other neural tube derivatives. These results show that activation of Wnt signaling influences facial shape through its impact on the forebrain and expression in the FEZ, and highlights the close relationship between morphogenesis of the forebrain and midface.
经典Wnt信号通路在正常颅面发育过程中发挥着多种关键作用，而其失调与面部结构出生缺陷有关。然而，Wnt信号通路何时以及如何影响表型变异，包括与疾病相关的变异，仍不清楚。一种潜在机制是通过Wnt信号通路在早期面部信号中心——额鼻外胚层区（FEZ）的模式形成中的作用，以及其随后对早期面部形态发生的调节。例如，Wnt信号通路可能直接改变FEZ中（）结构域的表达形状和/或幅度。为了验证这一想法，我们使用了一种编码的具有复制能力的禽肉瘤逆转录病毒（RCAS）来调节其在面部间充质中的表达。然后，我们使用碘对比微计算机断层扫描成像和三维（3D）几何形态计量学（3DGM），对处理过的胚胎和未处理的胚胎在FEZ的表达结构域的三维（3D）形状、面部原基和大脑形态的个体发育变化进行了量化和比较。我们发现，头部发育早期阶段表达的增加会在结构和信号分析水平之间产生形状上的相关变异。此外，激活的改变破坏了前脑与其他神经管衍生物之间的整合。这些结果表明，Wnt信号通路的激活通过其对前脑和FEZ中表达的影响来影响面部形状，并突出了前脑和中面部形态发生之间的密切关系。
