PUBLICATION
Lrrk2 modulation of Wnt signaling during zebrafish development
- Authors
- Wint, J.M., Sirotkin, H.I.
- ID
- ZDB-PUB-200706-14
- Date
- 2020
- Source
- Journal of neuroscience research 98(10): 1831-1842 (Journal)
- Registered Authors
- Sirotkin, Howard
- Keywords
- CRISPR-Cas9, Lrrk2, Parkinson's disease, Wnt, zebrafish
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Animals, Genetically Modified
- Embryonic Development/physiology*
- Fluorescent Dyes/analysis
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/analysis
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics*
- Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism*
- Mutation/physiology
- Wnt Signaling Pathway/physiology*
- Zebrafish
- Zebrafish Proteins/analysis
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism*
- PubMed
- 32623786 Full text @ J. Neurosci. Res.
Citation
Wint, J.M., Sirotkin, H.I. (2020) Lrrk2 modulation of Wnt signaling during zebrafish development. Journal of neuroscience research. 98(10):1831-1842.
Abstract
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 (lrrk2sbu304 ), the GTPase, and kinase domains (lrrk2sbu71 ) or the kinase domain (lrrk2sbu96 ). 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 lrrk2sbu304/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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping