PUBLICATION
Specific miRNA-GPCR networks regulate Sox9a/Sox9b activities to promote gonadal rejuvenation in zebrafish
- Authors
- Guo, H., Du, X., Zhang, Y., Wu, J., Wang, C., Li, M., Hua, X., Zhang, X.A., Yan, J.
- ID
- ZDB-PUB-190523-8
- Date
- 2019
- Source
- Stem cells (Dayton, Ohio) 37(9): 1189-1199 (Journal)
- Registered Authors
- Yan, Jizhou, Zhang, Ying
- Keywords
- aging, and self-renewal, differentiation, germline, miRNA, signal transduction, tissue regeneration
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Female
- Gene Expression Profiling/methods
- Gene Expression Regulation, Developmental
- Male
- MicroRNAs/genetics*
- Ovarian Follicle/growth & development
- Ovarian Follicle/metabolism
- Ovary/growth & development
- Ovary/metabolism*
- Receptors, G-Protein-Coupled/genetics*
- Receptors, G-Protein-Coupled/metabolism
- Rejuvenation
- SOX9 Transcription Factor/genetics*
- SOX9 Transcription Factor/metabolism
- Spermatogenesis/genetics
- Testis/growth & development
- Testis/metabolism*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 31116894 Full text @ Stem Cells
Citation
Guo, H., Du, X., Zhang, Y., Wu, J., Wang, C., Li, M., Hua, X., Zhang, X.A., Yan, J. (2019) Specific miRNA-GPCR networks regulate Sox9a/Sox9b activities to promote gonadal rejuvenation in zebrafish. Stem cells (Dayton, Ohio). 37(9):1189-1199.
Abstract
Fertility and endocrine function rely on a tightly regulated synchronicity within the hypothalamic-pituitary gonadal (HPG) axis, for which the sex gonad serves as the primary source of sex steroid hormones and germ cells. To maintain hormonal stasis and fertility throughout the lifespan, inducing gonadal stem cell renewal is an attractive strategy. The FSH/cAMP/MAPK/ Sox9 signaling axis and its regulated specific miRNAs are thought to regulate vertebrate gonadal development and sex differentiation, yet the regulatory networks are largely unknown. By genome-wide transcriptome mining and gonadal microinjections, we identify two GPCR- regulatory circuits: miR430a-Sox9a in the testis and miR218a-Sox9b in the ovary. Co-injection of a Sox9a-miR430a mixture promotes spermatogenesis, while Sox9b-miR218a mixture increases primordial ovarian follicles. Co- immunoprecipitation and mass spectrometry indicate that the two mixtures differentially modulate Sox9a/Sox9b multiple covalent modifications. We further reveal that miR430a and Sox9a synergistically activate testicular PKC/Akt signaling, while the miR218a and Sox9b mixture constrains ovary PKC/Akt signaling. pMIR-GFP reporter assays demonstrate that miR430a and miR218a target the 3'UTR of four GPCR targets (lgr4, grk5l, grk4, and grp157). Knockdown of these GPCR genes or two Sox9 genes alters miR430a and miR218a regulation in the above gonad-specific PKC and Akt signaling pathways. These results establish two specific miRNA-GPCR- Sox9 networks and provide mechanistic insight into gonadal differentiation and rejuvenation. SIGNIFICANCE STATEMENT: Accumulating evidence suggests that microRNAs and small molecule cocktails are able to manipulate cell fate and plasticity in stem cells and differentiated cells. However, phenotypic conversion of sex gonad requires intricate coordination of multiple somatic and germline lineages. Here, we performed zebrafish genome-wide transcriptome mining and found that gonadal injection of miR430a-Sox9a mixture and miR18-Sox9b mixture could increase the testis spermatogonia reserve and ovarian follicle reserve respectively. We predict that the miRNA-target pair data reported here will help identify more potential therapeutic targets and promote to develop new therapeutic interventions for aging-related ovarian failure and testicular regression in humans. © AlphaMed Press 2019.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping