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How do cell signal transduction pathways interact to control vertebrate tooth development? Calvin Park, Class of 2017 During early vertebrate embryo development, the cellular phenotypes and behaviors behind organ formation are shaped by many tiers of gene regulation, one of which is cell signaling. In tooth development, for example, cells communicate by secreting specific molecules that, when recognized by competent cells, initiate signal transduction leading to desired gene expression. Studies of signal transduction function in vertebrate tooth development have primarily investigated how the activity of individual cell signaling pathways influences dentition, concluding that Hedgehog and Retinoic Acid signaling, among others, are required for mammalian and fish tooth development. Investigations of how these pathways affect one another, however, have yielded inconclusive results and mainly focused on gene expression. As a step toward understanding how signaling pathways interact to influence vertebrate tooth development, a recent report demonstrated that developing mouse molars display a novel cusp phenotype following functional manipulation of several required signaling pathways (Harjunmaa et al. 2012). Building off of this work, the Jackman lab is investigating how manipulated activity of multiple signaling pathways affects first generation dentition during early zebrafish (Danio rerio) development. As part of this project, I specifically studied how the Hedgehog and Retinoic Acid cell signaling pathways interact to control early zebrafish tooth development. The Jackman lab has previously demonstrated that overactivating Retinoic Acid signaling during early zebrafish development results in the formation of supernumerary, pharyngeal teeth (Seritrakul et al. 2012), while early inhibition of Hedgehog signaling prevents tooth development or reduces tooth size (Yu et al. 2015). With knowledge of how functional manipulation of either signaling pathway alone affects early tooth development, comparative analyses of dental phenotypes resulting from combined pathway activity manipulation can broadly suggest how the pathways interact, if at all, in different aberrant signaling environments. Analysis of corresponding gene expression levels proportional to signaling activity can provide a more complete understanding of how each pathway’s activity regulation or influence on phenotype is affected by the signaling environment. This summer, I focused on combined overactivation of Hedgehog and Retinoic Acid signaling in early zebrafish development. Along with previous gene expression studies performed in the Jackman lab, the dental phenotypes I observed suggest that compensatory changes to Hedgehog signaling activity in the overactive Retinoic Acid signaling environment can influence the development of first generation zebrafish teeth. In the future, I would like to assess how Hedgehog activity is affected by early overactivation of other signal transduction pathways necessary for tooth development and to investigate if Hedgehog signaling manipulation can influence dental character in these unique signaling contexts. I am grateful to have had the opportunity to study vertebrate development and learn laboratory techniques applied to the zebrafish model system. As a pre-medical school student, I look forward to seeing how knowledge of cell signaling in vertebrate tooth development will be applied to medical research. Particularly fascinating is how this knowledge can be used to recreate the embryonic conditions necessary for regenerative dental therapy, given the latest human stem cell technological advances. Indeed, the future holds many mysteries and promises. Faculty Mentor: William R. Jackman Funded by the NIH Student Faculty Research Grant Fellowship and INBRE Summer Fellowship References Harjunmaa E, Kallonen A, Voutilainen M, Hämäläinen K, Mikkola ML, Jernvall J. 2012. On the difficulty of increasing dental complexity. Nature 483(7389): 324-7. Seritrakul P, Samarut E, Lama TT, Gibert Y, Laudet V, Jackman WR. 2012. Retinoic Acid expands the evolutionarily reduced dentition of zebrafish. FASEB J 26(12): 5014-24. Yu JC, Fox ZD, Crimp JL, Littleford HE, Jowdry AL, Jackman WR. 2015. Hedgehog signaling regulates dental papilla formation and tooth size during zebrafish odontogenesis. Dev Dyn 244(4): 577-90.
