TATTOO-seq delineates spatial and cell type-specific regulatory programs during limb patterning

Abstract

The coordinated differentiation of progenitor cells into specialized cell types and their spatial organization into distinct domains is central to embryogenesis. To investigate the interplay between differentiation and patterning, we developed an unbiased spatially resolved single-cell transcriptomics method. We applied this high-content and high-resolution approach to characterize the gene expression patterns that underlie the emergence of specialized cell types and their contribution to limb morphogenesis. Through independent registration of spatial position and molecular identity, we identified combinations of transcription factors predominantly associated with spatial position or cell type specification, and deconvolute their contribution to molecular phenotypes. We also show that alteration of a limb signaling center leads to a multi-scale re-organization of limb development, involving the loss of specific cell populations and the modulation of both the spatial distributions and the molecular identities of pre-existing cell states. Our results demonstrate how multi-dimensional single-cell spatially resolved molecular atlases can help understand the intricacies of organogenesis.