The proper positioning of organs during development is essential, yet little is known about the regulation of this process in mammals. Using murine tooth development as a model, we have found that cell migration plays a central role in positioning of the organ primordium. By combining lineage tracing, genetic cell ablation, and confocal live imaging, we identified a migratory population of Fgf8-expressing epithelial cells in the embryonic mandible. These Fgf8-expressing progenitors furnish the epithelial cells required for tooth development, and the progenitor population migrates toward a Shh-expressing region in the mandible, where the tooth placode will initiate. Inhibition of Fgf and Shh signaling disrupted the oriented migration of cells, leading to a failure of tooth development. These results demonstrate the importance of intraepithelial cell migration in proper positioning of an initiating organ.

Department of Cell and Tissue Biology University of California San Francisco 513 Parnassus Avenue San Francisco CA 94143 USA

Department of Orofacial Sciences and Program in Craniofacial Biology University of California San Francisco 513 Parnassus Avenue San Francisco CA 94143 USA; Department of Pediatrics and Institute for Human Genetics University of California San Francisco 513 Parnassus Avenue San Francisco CA 94143 USA

Department of Orofacial Sciences and Program in Craniofacial Biology University of California San Francisco 513 Parnassus Avenue San Francisco CA 94143 USA; Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the ASCR v v i Prague 4 14220 Czech Republic

Department of Orofacial Sciences and Program in Craniofacial Biology University of California San Francisco 513 Parnassus Avenue San Francisco CA 94143 USA; State Key Laboratory of Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu Sichuan 610041 China

Department of Psychiatry Nina Ireland Laboratory of Developmental Neurobiology University of California San Francisco 1500 4th Street San Francisco CA 94143 USA

Laboratory for Molecular Mechanisms of Thalamus Development RIKEN Brain Science Institute 2 1 Hirosawa Wako Saitama 351 0198 Japan

Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the ASCR v v i Prague 4 14220 Czech Republic

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