Notch signaling pathway in tooth shape variations throughout evolution

Evolutionary changes in vertebrates are linked to genetic alterations that often affect tooth-crown shape, which is a criterion of speciation events, especially in mammals. The Notch pathway is highly conserved between species and controls morphogenetic processes in most developing organs, including teeth. Epithelial loss of the Notch-ligand Jagged1 in developing mouse molars affects the location, size and interconnections of their cusps that lead to minor tooth-crown shape modifications convergent to those observed along Muridae evolution. RNA sequencing analysis revealed that these alterations are due to the modulation of more than 2000 genes and that Notch signaling is a hub for significant morphogenetic networks, such as Wnts and Fibroblast Growth Factors. The modeling of these tooth-crown changes in mutant mice, via a three-dimensional metamorphosis approach, allowed prediction of how Jagged1-associated mutations in humans could affect the morphology of their teeth. These results shed new light on Notch/Jagged1-mediated signaling as one of the crucial components for dental variations in evolution.脊椎动物的演化进程常与遗传变异存在关联，此类变异往往会影响牙冠形态，而牙冠形态是物种形成事件的重要判定依据，在哺乳动物类群中尤为显著。Notch信号通路（Notch pathway）在物种间高度保守，可调控绝大多数发育中器官的形态发生过程，牙齿亦包含其中。在发育中的小鼠磨牙内，上皮细胞中Notch配体Jagged1（Jagged1）的缺失会改变其牙尖的位置、大小与相互连接模式，最终引发牙冠形态的细微改变，该改变与鼠科（Muridae）演化过程中观测到的形态变化趋同。RNA测序（RNA sequencing）分析显示，上述牙冠形态变异源于超过2000个基因的表达调控，且Notch信号是Wnt信号通路、成纤维细胞生长因子（Fibroblast Growth Factors）等关键形态发生网络的核心调控枢纽。研究人员通过三维形态重塑方法对突变小鼠的牙冠形态变化进行建模，由此可预测人类体内Jagged1相关突变会如何影响其牙齿形态。本研究结果为阐明Notch/Jagged1介导的信号通路作为演化过程中牙齿形态变异的关键调控组分提供了全新视角。