Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA 94143, USA.
Development. 2011 Sep;138(18):4063-73. doi: 10.1242/dev.069195.
Much of our knowledge about mammalian evolution comes from examination of dental fossils, because the highly calcified enamel that covers teeth causes them to be among the best-preserved organs. As mammals entered new ecological niches, many changes in tooth number occurred, presumably as adaptations to new diets. For example, in contrast to humans, who have two incisors in each dental quadrant, rodents only have one incisor per quadrant. The rodent incisor, because of its unusual morphogenesis and remarkable stem cell-based continuous growth, presents a quandary for evolutionary biologists, as its origin in the fossil record is difficult to trace, and the genetic regulation of incisor number remains a largely open question. Here, we studied a series of mice carrying mutations in sprouty genes, the protein products of which are antagonists of receptor-tyrosine kinase signaling. In sprouty loss-of-function mutants, splitting of gene expression domains and reduced apoptosis was associated with subdivision of the incisor primordium and a multiplication of its stem cell-containing regions. Interestingly, changes in sprouty gene dosage led to a graded change in incisor number, with progressive decreases in sprouty dosage leading to increasing numbers of teeth. Moreover, the independent development of two incisors in mutants with large decreases in sprouty dosage mimicked the likely condition of rodent ancestors. Together, our findings indicate that altering genetic dosage of an antagonist can recapitulate ancestral dental characters, and that tooth number can be progressively regulated by changing levels of activity of a single signal transduction pathway.
我们对哺乳动物进化的了解主要来自对牙齿化石的研究，因为覆盖在牙齿上的高度钙化的釉质使它们成为保存最完好的器官之一。随着哺乳动物进入新的生态位，牙齿数量发生了许多变化，这可能是对新饮食的适应。例如，与人类每一个象限有两颗门齿不同，啮齿动物每个象限只有一颗门齿。由于啮齿动物的门齿具有不寻常的形态发生和显著的基于干细胞的连续生长，这给进化生物学家带来了一个难题，因为它在化石记录中的起源难以追踪，而且门齿数量的遗传调控仍然是一个很大的悬而未决的问题。在这里，我们研究了一系列携带 sprouty 基因突变的小鼠，其蛋白质产物是受体酪氨酸激酶信号的拮抗剂。在 sprouty 功能丧失突变体中，基因表达域的分裂和细胞凋亡的减少与门齿原基的细分以及其含有干细胞的区域的增殖有关。有趣的是，sprouty 基因剂量的变化导致门齿数量的分级变化，随着 sprouty 剂量的逐渐减少，牙齿数量逐渐增加。此外，在 sprouty 剂量大幅减少的突变体中，两个门齿的独立发育模拟了啮齿动物祖先的可能情况。总之，我们的研究结果表明，改变拮抗剂的遗传剂量可以再现祖先的牙齿特征，并且通过改变单个信号转导途径的活性水平可以逐渐调节牙齿数量。
