UCSF

The fossil record is widely informative about evolution, but fossils have not been systematically used to study the evolution of stem cells. Moreover, while the mechanisms underlying tooth development have been widely studied in model organisms, the role of genetic regulatory elements in patterning the different elements of the occlusal surface and crown height across species is not well understood. Here, I examined evolution of the rodent adult dental stem cell niche, which enables continuous growth (hypselodonty) of molar teeth. Moreover, I compared the variation in dental morphology across nine taxa of rodents to the variation in sequences of non-coding evolutionary conserved regions (ECRs) of Fgf3, 4, 8, 9, and 10 and the function of Fgf10 signaling on retention of molar stem cell niches. I studied the occurrences of 3500 North American fossil rodent specimens, ranging from 50 million years ago (mya) to 2 mya. I examined evolutionary changes in molar height to determine if evolution of continuously growing molars shows distinct patterns in the fossil record, and we found that hypselodont taxa emerged through intermediate forms of increasing crown height. Next, we designed a two-parameter Markov simulation model, which correctly accounted for molar height increases throughout the Cenozoic, and, moreover, evolution of hypselodonty. Finally, I correlated the variation in molar tooth cusp shape and the evolution of high molar crowns (hypsodonty) to the patterns of sequence variation in two ECRs, Fgf10ECR3 and Fgf9ECR1, respectively. By conducting luciferase and electrophoretic mobility shift assays, we determined that these ECRs could function as enhancers. Thus, by extension, the retention of the adult stem-cell niche appears to be a predictable quantitative rather than a stochastic qualitative process. Our analyses predict that hypselodonty will eventually become the dominant rodent phenotype. Mammalian dental morphology is under strong evolutionary pressure because of its importance for mastication and diet. My data suggest that emergence of hypsodonty and occlusal cusp patterning may have happened through the evolutionary changes in enhancers, such as Fgf9ECR1 and Fgf10ECR3, which affected the expression of major signaling molecules involved in tooth development.