PUBLICATION
A 12-lipoxygenase-Gpr31 signaling axis is required for pancreatic organogenesis in the zebrafish
- Authors
- Hernandez-Perez, M., Kulkarni, A., Samala, N., Sorrell, C., El, K., Haider, I., Mukhtar Aleem, A., Holman, T.R., Rai, G., Tersey, S.A., Mirmira, R.G., Anderson, R.M.
- ID
- ZDB-PUB-201002-29
- Date
- 2020
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34(11): 14850-14862 (Journal)
- Registered Authors
- Anderson, Ryan
- Keywords
- 12-lipoxygenase, Gpr31, exocrine tissue, pancreas development, zebrafish, β cells
- MeSH Terms
-
- Animals
- Arachidonic Acid/metabolism
- Lipoxygenases/genetics
- Lipoxygenases/metabolism*
- Organogenesis*
- Pancreas/embryology
- Pancreas/metabolism*
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism*
- Signal Transduction*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 32918516 Full text @ FASEB J.
Citation
Hernandez-Perez, M., Kulkarni, A., Samala, N., Sorrell, C., El, K., Haider, I., Mukhtar Aleem, A., Holman, T.R., Rai, G., Tersey, S.A., Mirmira, R.G., Anderson, R.M. (2020) A 12-lipoxygenase-Gpr31 signaling axis is required for pancreatic organogenesis in the zebrafish. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 34(11):14850-14862.
Abstract
12-Lipoxygenase (12-LOX) is a key enzyme in arachidonic acid metabolism, and alongside its major product, 12-HETE, plays a key role in promoting inflammatory signaling during diabetes pathogenesis. Although 12-LOX is a proposed therapeutic target to protect pancreatic islets in the setting of diabetes, little is known about the consequences of blocking its enzymatic activity during embryonic development. Here, we have leveraged the strengths of the zebrafish-genetic manipulation and pharmacologic inhibition-to interrogate the role of 12-LOX in pancreatic development. Lipidomics analysis during zebrafish development demonstrated that 12-LOX-generated metabolites of arachidonic acid increase sharply during organogenesis stages, and that this increase is blocked by morpholino-directed depletion of 12-LOX. Furthermore, we found that either depletion or inhibition of 12-LOX impairs both exocrine pancreas growth and unexpectedly, the generation of insulin-producing β cells. We demonstrate that morpholino-mediated knockdown of GPR31, a purported G-protein-coupled receptor for 12-HETE, largely phenocopies both the depletion and the inhibition of 12-LOX. Moreover, we show that loss of GPR31 impairs pancreatic bud fusion and pancreatic duct morphogenesis. Together, these data provide new insight into the requirement of 12-LOX in pancreatic organogenesis and islet formation, and additionally provide evidence that its effects are mediated via a signaling axis that includes the 12-HETE receptor GPR31.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping