Regulatory feedback between VEGF and ERK pathways controls tip-cell expression during sea urchin skeletogenesis

The sea urchin skeletogenic gene regulatory network (GRN) shows high similarity to the GRN that controls vertebrate vascularization, suggesting that sea urchin biomineralization evolved through co-option of an ancestral tubulogenesis GRN. During vertebrate angiogenesis, vascular endothelial growth factor (VEGF) signaling activates the extracellular-signal regulated kinase (ERK) pathway, which drives gene expression at the tip cells of sprouting blood vessels. Sea urchin VEGF and ERK pathways drive skeletal elongation, but the regulatory interactions between them remain unclear. Here, we reveal positive-feedback circuitry where VEGF signaling activates ERK in the skeletogenic cells near the tips of the skeletal rods, and ERK drives the expression of the VEGF receptor, VEGFR, in these cells. Furthermore, ERK is essential for the transcription of the key skeletogenic transcription factor Ets1/2 and the spicule matrix protein SM50 at the tips of the skeletal rods, while clearing SM50 from the cells at the back. Comparing VEGF and ERK regulation of tip cell expression between vertebrate angiogenesis and sea urchin skeletogenesis illuminates similarities and differences that possibly underlie the co-option of the ancestral tubulogenesis GRN for biomineralization.