Sulfatase modifying factors control the timing of zebrafish gastrulation morphogenesis

To shape the emerging body plan, morphogenetic cell movements must be coordinated not only in space, but also in time. Convergence and Extension (C&E) movements that elongate the anteroposterior axis initiate with precise timing during vertebrate gastrulation, but the mechanisms controlling their onset remain unknown. We examined this question using zebrafish embryonic explants that faithfully recapitulate C&E cell movements and their precise timing in culture, in isolation from other gastrulation movements. We determined that new transcription is required at gastrulation onset for C&E in explants and identified sulfatase modifying factor 2 (sumf2) as a candidate trigger of C&E onset. sumf2 encodes for pFGE, the paralog and inhibitor of the Formylglycine Generating Enzyme (FGE, encoded by sumf1), which is the key activator of all sulfatase enzymes. In zebrafish embryos and explants, sumf1 expression declines just as sumf2 is expressed, leading to decreased sulfatase activity and increased sulfation of their heparan sulfate proteoglycan (HSPG) substrates. We found that overexpression of sumf1 and sumf2 causes delayed or precocious C&E onset, respectively, whereas mutations in sumf1 and sumf2 shift C&E timing in the opposite direction. We further identified Sulf1, an extracellular sulfatase that modifies HSPGs, as the key effector by which sumf1 and sumf2 control C&E timing. Accordingly, reduced or increased levels of sulfated heparan sulfate similarly shift C&E onset and suppress sumf1 and sumf2 mutant phenotypes. Together, our work supports a model in which sumf2 expression at zebrafish gastrulation onset reduces sulfatase activity, rewriting HSPG sulfation patterns to promote and/or permit C&E morphogenesis.