Autotaxin/Lpar3 signaling regulates Kupffer's vesicle formation and left-right asymmetry in zebrafish
- Authors
- Lai, S.L., Yao, W.L., Tsao, K.C., Houben, A.J., Albers, H.M., Ovaa, H., Moolenaar, W.H., and Lee, S.J.
- ID
- ZDB-PUB-121102-39
- Date
- 2012
- Source
- Development (Cambridge, England) 139(23): 4439-4448 (Journal)
- Registered Authors
- Lai, Shih-Lei (Ben), Lee, Shyh-Jye
- Keywords
- Autotaxin, Lysophosphatidic acid, Calcium, Left-right asymmetry, Zebrafish
- MeSH Terms
-
- Animals
- Body Patterning/genetics*
- Calcium Signaling
- Cell Nucleus/metabolism
- Gene Expression Regulation, Developmental
- Gene Knockdown Techniques
- Isoxazoles/pharmacology
- Lysophospholipids/metabolism*
- Morphogenesis
- Morpholinos/genetics
- Morpholinos/pharmacology
- Phosphoric Diester Hydrolases/genetics
- Phosphoric Diester Hydrolases/metabolism*
- Propionates/pharmacology
- Receptors, Lysophosphatidic Acid/genetics
- Receptors, Lysophosphatidic Acid/metabolism*
- Receptors, Purinergic P2/genetics
- Receptors, Purinergic P2/metabolism*
- Wnt Signaling Pathway
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- beta Catenin/metabolism
- PubMed
- 23095890 Full text @ Development
Left-right (L-R) patterning is essential for proper organ morphogenesis and function. Calcium fluxes in dorsal forerunner cells (DFCs) are known to regulate the formation of Kupffer's vesicle (KV), a central organ for establishing L-R asymmetry in zebrafish. Here, we identify the lipid mediator lysophosphatidic acid (LPA) as a regulator of L-R asymmetry in zebrafish embryos. LPA is produced by Autotaxin (Atx), a secreted lysophospholipase D, and triggers various cellular responses through activation of specific G protein-coupled receptors (Lpar1-6). Knockdown of Atx or LPA receptor 3 (Lpar3) by morpholino oligonucleotides perturbed asymmetric gene expression in lateral plate mesoderm and disrupted organ L-R asymmetries, whereas overexpression of lpar3 partially rescued those defects in both atx and lpar3 morphants. Similar defects were observed in embryos treated with the Atx inhibitor HA130 and the Lpar1-3 inhibitor Ki16425. Knockdown of either Atx or Lpar3 impaired calcium fluxes in DFCs during mid-epiboly stage and compromised DFC cohesive migration, KV formation and ciliogenesis. Application of LPA to DFCs rescued the calcium signal and laterality defects in atx morphants. This LPA-dependent L-R asymmetry is mediated via Wnt signaling, as shown by the accumulation of β-catenin in nuclei at the dorsal side of both atx and lpar3 morphants. Our results suggest a major role for the Atx/Lpar3 signaling axis in regulating KV formation, ciliogenesis and L-R asymmetry via a Wnt-dependent pathway.