PUBLICATION
Testosterone acts through membrane protein GPRC6A to cause cardiac edema in zebrafish embryos
- Authors
- Zadmajid, V., Shahriar, S., Gorelick, D.A.
- ID
- ZDB-PUB-241101-2
- Date
- 2024
- Source
- Development (Cambridge, England) 151(23): (Journal)
- Registered Authors
- Gorelick, Daniel, Zadmajid, Vahid
- Keywords
- Androgen receptor, GPRC6A, Heart development, Membrane steroid signaling, Zebrafish
- Datasets
- GEO:GSE274852
- MeSH Terms
-
- Receptors, G-Protein-Coupled*/genetics
- Receptors, G-Protein-Coupled*/metabolism
- Androgens/metabolism
- Androgens/pharmacology
- Heart/drug effects
- Heart/embryology
- Receptors, Androgen/genetics
- Receptors, Androgen/metabolism
- Testosterone*/metabolism
- Testosterone*/pharmacology
- Mutation/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Signal Transduction/drug effects
- Animals
- Gene Expression Regulation, Developmental/drug effects
- Zebrafish*/embryology
- Zebrafish*/metabolism
- Edema, Cardiac*/genetics
- Edema, Cardiac*/metabolism
- Edema, Cardiac*/pathology
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- PubMed
- 39479956 Full text @ Development
Citation
Zadmajid, V., Shahriar, S., Gorelick, D.A. (2024) Testosterone acts through membrane protein GPRC6A to cause cardiac edema in zebrafish embryos. Development (Cambridge, England). 151(23):.
Abstract
Androgens are classically thought to act through intracellular androgen receptors (AR/NR3C4), but they can also trigger non-genomic effects via membrane proteins. Although several membrane androgen receptors have been characterized in vitro, their functions in vivo remain unclear. Using a chemical-genetic screen in zebrafish, we found that GPRC6A, a G-protein coupled receptor, mediates non-genomic androgen actions during embryonic development. Exposure to androgens (androstanedione, DHT, and testosterone) caused cardiac edema or tail curvature in wild-type embryos, as well as in ar mutants, suggesting AR-independent pathways. We then mutated putative membrane androgen receptors (gprc6a, hcar1-4, and zip9) and found that only gprc6a mutants exhibited a significant reduction in cardiac edema following testosterone exposure. Additionally, co-treatment of wild-type embryos with testosterone and GPRC6A antagonists significantly suppressed the cardiac edema phenotype. Using RNA-seq and RNA rescue approaches, we found that testosterone-GPRC6A causes cardiac phenotypes by reducing Pak1 signaling. Our results indicate that testosterone induces cardiac edema in zebrafish embryos through GPRC6A, independent of nuclear androgen receptors, highlighting a novel non-genomic androgen signaling pathway in embryonic development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping