Mechanisms of Wnt5a‐Ror Signaling in Development and Disease

Abstract

Wnt5a‐Ror signaling is a conserved developmental pathway that regulates morphogenetic processes during vertebral embryonic development, and dysfunction of the pathway causes a number of human disorders, including Robinow syndrome. The mechanisms of Wnt5a‐Ror signaling remain poorly understood. Using a large‐scale proteomic screen, we identified the E3 ubiquitin ligase Pdzrn3 as a new regulatory target that is degraded upon pathway activation in a beta‐catenin independent, ubiquitin‐proteasome system dependent manner. Using this discovery, we developed a flow cytometry‐based reporter to monitor Pdzrn3 abundance and delineated a signaling cascade involving Frizzled, Dishevelled, Casein kinase 1, and Glycogen synthase kinase 3 that regulates Pdzrn3 degradation. Genetic epistasis analysis suggests that Pdzrn3 resides downstream of Dishevelled and independently of Kif26b, a previously identified Wnt5a‐Ror regulatory target. Further, we discovered that Pdzrn3 degradation requires Wnt5a‐dependent phosphorylation of its C‐terminal LNX3H domain, which is conserved in several Pdzrn3 homologs and likely functions as a novel Wnt5a‐responsive domain. Collectively, this work establishes a new Wnt5a‐Ror signaling cascade involving Pdzrn3 phosphorylation and degradation.Support or Funding InformationNIH Grant 1R35GM119574