Timed mesodermal FGF and BMP govern the multi-step thyroid specification

The thyroid plays an essential role in homeostasis and development, but the extrinsic regulation of its embryonic development remains poorly understood. Recently, we have identified the FGF and BMP pathways to be crucial for thyroid specification and have confirmed the hypothesis that the cardiac mesoderm provides the FGF and BMP ligands to regulate this process. However, it is not clear how these ligands control thyroid specification. To study the molecular mechanisms underlying early thyroid development, we combined a pharmacological approach in zebrafish embryos with genetic models, to modulate the activity of the FGF and BMP pathways at different embryonic stages. We first characterized the expression of the transcription factors pax2a and nkx2.4b - the two main early thyroid markers - in the anterior foregut endoderm and observed that pax2a was expressed from 18 hours post fertilization (hpf) and marked a large endodermal cell population while nkx2.4b was expressed from 24 hpf and marked only a subset of the pax2a-positive endodermal cells. Interestingly, the activity profiles of FGF and BMP coincided with the detection of pax2a and nkx2.4b expression, respectively. Brief modulations of the FGF and/or BMP pathways support the hypothesis that the FGF pathway regulates the expression of pax2a and the BMP pathway regulates the expression of nkx2.4b. Furthermore, inhibition of the BMP pathway during early segmentation has dramatic effects on thyroid specification, probably via the FGF pathway. Together with our previous observations, we propose here, an updated model of early thyroid development in which the foregut endoderm receives several synchronized waves of FGF and BMP signals from the cardiac mesoderm, which result in sequential activation of pax2a and nkx2.4b gene expression and subsequent thyroid specification.