Resolving thyroid lineage cell trajectories merging into a dual endocrine gland in mammals

The thyroid has a remarkable evolution, transforming from an exocrine constituent of the chordate endostyle to an endocrine gland in basal vertebrates. In mammals, a second endocrine cell type of presumed neural crest origin appears, although recent lineage tracing has firmly established thyroid C-cells are also endoderm-derived. Here, we characterize the global gene expression in both embryonic thyroid lineages at single-cell level and identify lineage-specific transcription factors and their network regulation of target genes implicated in thyroid development into a dual endocrine organ. Merging of the pharyngeal pouch-derived ultimobranchial bodies with the midline thyroid primordium is an ordered process featuring basement membrane dynamics and epithelial-mesenchymal plasticity required for precursor cells to disseminate and properly integrate, thus forming the typical histoarchitecture of thyroid follicles and parafollicular C-cells. Synchronous lineage growth of compound follicles is recapitulated in mixed-type thyroid carcinoma in which only the neuroendocrine tumor cells escape the follicle basement membrane boundaries and become invasive adopting a C-cell precursor-like migratory phenotype.