Kctd15 inhibits neural crest formation by attenuating Wnt/beta-catenin signaling output

Neural crest (NC) precursors are stem cells that are capable of forming many cell types after migration to different locations in the embryo. NC and placodes form at the neural plate border (NPB). The Wnt pathway is essential for specifying NC versus placodal identity in this cell population. Here we describe the BTB domain-containing protein Potassium channel tetramerization domain containing 15 (Kctd15) as a factor expressed in the NPB that efficiently inhibits NC induction in zebrafish and frog embryos. Whereas overexpression of Kctd15 inhibited NC formation, knockdown of Kctd15 led to expansion of the NC domain. Likewise, NC induction by Wnt3a plus Chordin in Xenopus animal explants was suppressed by Kctd15, but constitutively active beta-catenin reversed Kctd15-mediated suppression of NC induction. Suppression of NC induction by inhibition of Wnt8.1 was rescued by reduction of Kctd15 expression, linking Kctd15 action to the Wnt pathway. We propose that Kctd15 inhibits NC formation by attenuating the output of the canonical Wnt pathway, thereby restricting expansion of the NC domain beyond its normal range.