Abstract
Wnt5a-Ror signaling constitutes a developmental pathway crucial for embryonic tissue morphogenesis, reproduction and adult tissue regeneration, yet the molecular mechanisms by which the Wnt5a-Ror pathway mediates these processes are largely unknown. Using a proteomic screen, we identify the kinesin superfamily protein Kif26b as a downstream target of the Wnt5a-Ror pathway. Wnt5a-Ror, through a process independent of the canonical Wnt/β-catenin-dependent pathway, regulates the cellular stability of Kif26b by inducing its degradation via the ubiquitin-proteasome system. Through this mechanism, Kif26b modulates the migratory behavior of cultured mesenchymal cells in a Wnt5a-dependent manner. Genetic perturbation of Kif26b function in vivo caused embryonic axis malformations and depletion of primordial germ cells in the developing gonad, two phenotypes characteristic of disrupted Wnt5a-Ror signaling. These findings indicate that Kif26b links Wnt5a-Ror signaling to the control of morphogenetic cell and tissue behaviors in vertebrates and reveal a new role for regulated proteolysis in noncanonical Wnt5a-Ror signal transduction.
Highlights
The Wnt family of extracellular signaling factors orchestrates diverse developmental processes during both embryogenesis and adult tissue homeostasis
We previously showed that embryonic day 12.5 (E12.5) mouse embryonic fibroblasts (MEFs) are a useful physiologically-relevant system for studying Wnt5a-Ror signaling
Are these cells derived from mesenchymal tissues that undergo active Wnt5a-Ror signaling in vivo, they continue to express high levels of endogenous Wnt5a, Ror1, Ror2 and Dvl proteins in culture and undergo autocrine/paracrine Wnt5a-Ror signaling without the addition of exogenous Wnt5a (Ho et al, 2012)
Summary
The Wnt family of extracellular signaling factors orchestrates diverse developmental processes during both embryogenesis and adult tissue homeostasis. Developmental Biology and Stem Cells activating multiple biochemically distinct pathways to regulate diverse cell biological processes (Veeman et al, 2003; Semenov et al, 2007). Dysregulation of Wnt5a signaling leads to birth defects and is associated with multiple pathological processes in the adult including cancer metastasis and inflammatory diseases such as atherosclerosis (Kurayoshi et al, 2006; Da Forno et al, 2008; Yamamoto et al, 2010; Jin et al, 2012; Lu et al, 2012; Bhatt and Malgor, 2014; Ford et al, 2014; Lin et al, 2014; Lu et al, 2014; Qin et al, 2015)
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