Wnt5a–Ror–Dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis

Abstract

Wnts make up a large family of extracellular signaling molecules that play crucial roles in development and disease. A subset of noncanonical Wnts signal independently of the transcription factor β-catenin by a mechanism that regulates key morphogenetic movements during embryogenesis. The best characterized noncanonical Wnt, Wnt5a, has been suggested to signal via a variety of different receptors, including the Ror family of receptor tyrosine kinases, the Ryk receptor tyrosine kinase, and the Frizzled seven-transmembrane receptors. Whether one or several of these receptors mediates the effects of Wnt5a in vivo is not known. Through loss-of-function experiments in mice, we provide conclusive evidence that Ror receptors mediate Wnt5a-dependent processes in vivo and identify Dishevelled phosphorylation as a physiological target of Wnt5a–Ror signaling. The absence of Ror signaling leads to defects that mirror phenotypes observed in Wnt5a null mutant mice, including decreased branching of sympathetic neuron axons and major defects in aspects of embryonic development that are dependent upon morphogenetic movements, such as severe truncation of the caudal axis, the limbs, and facial structures. These findings suggest that Wnt5a–Ror–Dishevelled signaling constitutes a core noncanonical Wnt pathway that is conserved through evolution and is crucial during embryonic development.

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Knocking out noncanonical receptors such as RYK, RORs and VANGLs results in defective axonal guidance and branching and neural tube defects [76][77][78].…”

“…Axon branching defect in ROR1/2 DKO mice [77] RYK Axon guidance defects in KO mice [76] Cleavage regulates neuronal differentiation [62] Required for induction of GABAergic neurons & inhibition of oligodendrogenesis [63] PTK7 Implicated in neural tube closure and stereociliary bundle orientation Required for neuromuscular synapse formation [103] LRP6 Neural tube closure defects and mid/hindbrain deficiencies in KO mice…”

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

“…S5). Although the former transcript possesses a very early termination codon due to a frame shift in exon 5, the latter transcript can produce a truncated ROR1 protein with a 96-aa deletion within its Ig-like domain (13). Similarly to MEFs, both variants were present in mutant mouse inner ears, with the shortest transcript more abundantly expressed (SI Appendix, Fig.…”

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

“…Indeed, different defined pathways, such as PCP and Wnt5A-ROR, demonstrate comparable signal cascade and could therefore be regarded as virtually identical. [19][20][21] The PCP pathway is involved in developmental processes such as regulation of cell polarity, movement, and orientation. This pathway signals via small GTPases such as RHOA and RAC1 and the JUN-N-terminal kinase leading to the activation of JUN-N-terminal kinase depending transcription factors such as ATF2.…”