Lysosomal degradation of the maternal dorsal determinant Hwa safeguards dorsal body axis formation

The Spemann and Mangold Organizer (SMO) is of fundamental importance for dorsal ventral body axis formation during vertebrate embryogenesis. Maternal Huluwa (Hwa) has been identified as the dorsal determinant that is both necessary and sufficient for SMO formation. However, it remains unclear how Hwa is regulated. Here, we report that the E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) is essential for restricting the spatial activity of Hwa and therefore correct SMO formation in Xenopus laevis . ZNRF3 interacts with and ubiquitinates Hwa, thereby regulating its lysosomal trafficking and protein stability. Perturbation of ZNRF3 leads to the accumulation of Hwa and induction of an ectopic axis in embryos. Ectopic expression of ZNRF3 promotes Hwa degradation and dampens the axis-inducing activity of Hwa. Thus, our findings identify a substrate of ZNRF3, but also highlight the importance of the regulation of Hwa temporospatial activity in body axis formation in vertebrate embryos. SYNOPSIS The transmembrane E3 ubiquitin ligases ZNRF3 ubiquitinates and promotes the lysosomal degradation of the dorsal determinant Huluwa (Hwa), and ultimately safeguards dorsal body axis formation during vertebrate embryogenesis. ZNRF3 restricts the spatial activity of Hwa in Xenopus laevis . ZNRF3 interacts with and ubiquitinates Hwa. ZNRF3 clears Hwa from plasma membrane and promotes its lysosomal degradation. Graphical Abstract The transmembrane E3 ubiquitin ligases ZNRF3 ubiquitinates and promotes the lysosomal degradation of the dorsal determinant Huluwa (Hwa), and ultimately safeguards dorsal body axis formation during vertebrate embryogenesis.