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Lrrk2 modulation of Wnt signaling during zebrafish development
Author(s) -
Wint Jinelle M.,
Sirotkin Howard I.
Publication year - 2020
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.24687
Subject(s) - lrrk2 , wnt signaling pathway , biology , zebrafish , microbiology and biotechnology , gtpase , scaffold protein , genetics , signal transduction , gene , mutation
Mutations in leucine‐rich repeat kinase 2 ( lrrk2 ) are the most common genetic cause of Parkinson's disease. Difficulty in elucidating the pathogenic mechanisms resulting from disease‐associated Lrrk2 variants stems from the complexity of Lrrk2 function and activities. Lrrk2 contains multiple protein–protein interacting domains, a GTPase domain, and a kinase domain. Lrrk2 is implicated in many cellular processes including vesicular trafficking, autophagy, cytoskeleton dynamics, and Wnt signaling. Here, we generated a zebrafish lrrk2 allelic series to study the requirements for Lrrk2 during development and to dissect the importance of its various domains. The alleles are predicted to encode proteins that either lack all functional domains ( lrrk2 sbu304 ) , the GTPase, and kinase domains ( lrrk2 sbu71 ) or the kinase domain ( lrrk2 sbu96 ). All three lrrk2 mutants are viable, morphologically normal, and display wild‐type‐like locomotion. Because Lrrk2 modulates Wnt signaling in some contexts, we assessed Wnt signaling in all three mutant lines. Analysis of Wnt signaling by studying the expression of target genes using whole mount RNA in situ hybridization and a transgenic Wnt reporter revealed wild‐type domains of Wnt activity in each of the mutants. However, we found that Wnt pathway activation is attenuated in lrrk2 sbu304/sbu304 , which lacks both scaffolding and catalytic domains, but not in the other alleles during late embryogenesis. This supports a model in which Lrrk2 scaffolding functions are key to a context‐dependent role in promoting canonical Wnt signaling.