Modulation of Fgf3 dosage in mouse and men mirrors evolution of mammalian dentition

Abstract

A central challenge in evolutionary biology is understanding how genetic mutations underlie morphological changes. Because highly calcified enamel enables preservation of detailed dental features, studying tooth morphology enables this question to be addressed in both extinct and extant species. Previous studies have found that mutant mice can have severe abnormalities in tooth morphology, and several authors have explored the evolutionary implications of tooth number modifications in mutants. However, although they can potentially shed much light on evolutionary mechanisms, anomalies in tooth shape remain poorly studied. Here, we report that alterations in dosage of the Fgf3 gene cause morphological changes in both genetically engineered mutant mice and in human patients. By comparing the dental morphologies in mice and humans carrying Fgf3 mutations with primitive rodent and primate fossils, we determined that decreases in dosage of Fgf3 lead to phenotypes that resemble the progressive reappearance of ancestral morphologies. We propose that modifications in the FGF signaling pathway have played an important role in evolution of mammalian dentition by giving rise to new cusps and interconnecting cusps by new crests. We anticipate that our multidisciplinary study will advance the detailed correlation of subtle dental modifications with genetic mutations in a variety of mammalian lineages. dental morphology ͉ Muroidea ͉ primates

Tooth shape formation and tooth renewal: evolving with the same signals

“…In the case of Spry2 and Spry4, which are intracellular feedback regulators of FGFs, cusp morphology is subtly altered (Klein et al, 2006). By contrast, analyses of the effects of loss of function of Fgf3 signaling in mouse and human molars show that the last developing cusps are reduced or missing (Charles et al, 2009). In the case of human upper molars, the last developing and evolutionarily newest cusp in the ancestry of primates, the hypocone, is missing (Charles et al, 2009).…”

“…By contrast, analyses of the effects of loss of function of Fgf3 signaling in mouse and human molars show that the last developing cusps are reduced or missing (Charles et al, 2009). In the case of human upper molars, the last developing and evolutionarily newest cusp in the ancestry of primates, the hypocone, is missing (Charles et al, 2009). Fgf3 is expressed in the developing mouse molars in the primary enamel knot and in the underlying dental mesenchyme, whereas Spry2 is expressed in the dental epithelium, including the enamel knot and Spry4 in the mesenchyme (Klein et al, 2006).…”

Deletion of Osr2 Partially Rescues Tooth Development in Runx2 Mutant Mice

“…5E-H). Fgf3 mutations in mice or humans were associated with abnormalities in tooth crown size or cusp patterning (Wang et al 2007;Charles et al 2009). However, the differences in Fgf3 expression alone could not account for the differences in molar tooth morphogenesis between the Osr2…”

Roles of dental development and adaptation in rodent evolution

“…Even though this dental pattern has been interpreted as a specialization to an abrasive diet 10 , little is actually known about the factors contributing to the parallel occurrences of stephanodonty over the course of murine evolution, especially the putative function of additional longitudinal crests during food processing. Moreover, the genetic aetiology and the underlying mechanisms involved in the formation of crests remain undescribed, inasmuch as most studies have mainly focused on cusp appearance and development [11][12][13][14] . The ectodysplasin (Eda) signalling pathway is required for normal development of organs of ectodermal origin, such as hair, exocrine glands and teeth [15][16][17][18] .…”