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dc.contributor.advisorMaas, Richard Louis
dc.contributor.authorO'Connell, Daniel Joseph
dc.date.accessioned2013-02-25T15:10:00Z
dc.date.issued2013-02-25
dc.date.submitted2011
dc.identifier.citationO'Connell, Daniel Joseph. 2011. An Epithelial-Mesenchymal Gene Regulatory Network that Controls Tooth Organogenesis. Doctoral dissertation, Harvard University.en_US
dc.identifier.otherhttp://dissertations.umi.com/gsas.harvard:10024en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10336924
dc.description.abstractMany vertebrate organs form via the sequential, reciprocal exchange of signaling molecules between juxtaposed epithelial (E) and mesenchymal (M) tissues. For example, the instructive signaling potential for tooth development (odontogenesis) resides in the dental epithelium at the initiation-stage, and subsequently shifts to the dental mesenchyme one day later at the bud-stage. However, the properties of the gene regulatory networks (GRNs) that control the signaling dynamics during epithelial-mesenchymal (E-M) interactions in organogenesis are largely unknown. This dissertation describes an interdisciplinary effort between developmental and systems biology to elucidate the E-M GRN that controls early odontogenesis. The results provide a molecular mechanism for the longstanding paradigm of sequential, reciprocal E-M tissue interactions in development. We generated large-scale spatiotemporal gene expression data for the developing mouse tooth. Surprisingly, the shift in signaling molecule expression from E to M is accompanied by a striking concordance in genome-wide expression changes in both E-M compartments as development proceeds. We hypothesized that since diffusible signaling molecules can act on either E or M independent of their tissue site of synthesis, signaling molecules are uniquely able to simultaneously synchronize and couple the transcriptional dynamics and hence the developmental progression of E and M. To identify the unifying mechanism behind concordant E and M genome-wide expression changes in the face of the discordant expression changes in signaling molecule expression, we developed a novel probabilistic technique that integrates regulatory evidence from microarray gene expression data and the literature to determine the E-M GRN for early tooth development. This GRN contains a uniquely configured E-M Wnt/Bmp feedback circuit in which the Wnt and Bmp signaling pathways in E cross-regulate the expression of Wnt and Bmp4 signaling molecules, whereas both pathways jointly regulate Bmp4 expression in M. We validated the Wnt/Bmp feedback circuit in vivo using compound genetic mutations in mice that either short-circuit or break the circuit, and used mathematical modeling to show how the structure of the Wnt/Bmp feedback circuit can account for reciprocal signaling dynamics. Collectively, these results provide a simple mechanistic framework for how simultaneous signal transduction in E-M compartments can account for the signaling dynamics in organogenesis.en_US
dc.language.isoen_USen_US
dash.licenseMETA_ONLY
dc.subjectgeneticsen_US
dc.subjectepithelial-mesenchymal interactionsen_US
dc.subjectgeneticsen_US
dc.subjectgene regulatory networken_US
dc.subjectorganogenesisen_US
dc.subjectsignalingen_US
dc.subjecttooth developmenten_US
dc.titleAn Epithelial-Mesenchymal Gene Regulatory Network that Controls Tooth Organogenesisen_US
dc.typeThesis or Dissertationen_US
dash.depositing.authorO'Connell, Daniel Joseph
dash.embargo.until10000-01-01
thesis.degree.date2011en_US
thesis.degree.disciplineGeneticsen_US
thesis.degree.grantorHarvard Universityen_US
thesis.degree.leveldoctoralen_US
thesis.degree.namePh.D.en_US
dc.contributor.committeeMemberIngber, Donalden_US
dc.contributor.committeeMemberKreidberg, Jordanen_US
dc.contributor.committeeMemberDrummond, Iainen_US
dc.contributor.committeeMemberChai, Yangen_US
dash.contributor.affiliatedO'Connell, Daniel Joseph


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