Abstract
The remarkable evolution of teeth morphological complexity represents a giant leap for vertebrate. Despite its importance in life history, the understanding of spatiotemporal organization of teeth remains rudimentary. Herein, a high-resolution genome-wide molecular patterning of lineage allocation and cellular organization in tooth morphogenesis is described, constructed by integrating spatial transcriptome and single-cell RNA sequencing. Twelve spatial compartments and seventeen heterogeneous cell clusters linked to tooth morphogenic milestones are identified. Eighty-eight percent of total lineage species has already appeared in the initial tooth bud rather than the generally considered sequential emergence. A previously unrecognized sprouting-like patterning mode of the dental papilla is discovered, that the inner compartment can break through the outer shell compartment to build up the final papilla cusp. Meanwhile, the continuum differentiation hierarchies of enamel knots in time and space are revealed. Furthermore, the regulatory network directing tooth morphogenesis is established, whereby a series of mechanotransduction signals are spatiotemporally involved beyond the well-established classical odontogenesis signals. Finally, genes underlying tooth dysplasia are successfully tracked to highly specific time points and cell types. The results raise the idea that tooth morphogenesis is orchestrated by mechanical niches combined with biochemical signaling.