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Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
Published on: January 2, 2018
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The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells
Thomas X Garcia1,2, Parag Parekh1, Pooja Gandhi1
11 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, MD Anderson Cancer Center , Houston, Texas.
Stem Cells and Development
|January 5, 2017
Summary
NOTCH signaling in Sertoli cells, activated by testicular stem cells via JAG1, limits sperm production by repressing GDNF expression through HES1 and HEY1. This reveals a negative feedback loop regulating spermatogenesis.
Area of Science:
- Reproductive biology
- Stem cell biology
- Molecular endocrinology
Background:
- Sertoli cells regulate spermatogonial stem cells (SSCs) in the testis niche.
- Glial cell line-derived neurotrophic factor (GDNF) is crucial for SSC self-renewal and expansion.
- NOTCH signaling in Sertoli cells has been linked to limiting stem/progenitor cell numbers.
Purpose of the Study:
- To elucidate the regulatory mechanisms of GDNF in the testicular stem cell niche.
- To determine the role and pathway of NOTCH signaling in Sertoli cells concerning spermatogenesis.
- To investigate the feedback regulation between testicular stem/progenitor cells and Sertoli cells.
Main Methods:
- Utilized a double-mutant mouse model to study NOTCH signaling.
- Performed Dual luciferase assays to assess transcriptional activity.
- Conducted chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) to analyze gene promoter binding.
- Investigated in vivo and in vitro interactions between stem cells and Sertoli cells.
Main Results:
- Confirmed that NOTCH signaling in Sertoli cells operates exclusively through the canonical pathway.
- Demonstrated that NOTCH targets HES1 and HEY1 directly repress GDNF expression by binding to its promoter.
- Showed that HES1 and HEY1 antagonize the stimulatory effects of FSH/cAMP on GDNF.
- Identified that testicular stem/progenitor cells activate NOTCH signaling in Sertoli cells via surface JAG1.
Conclusions:
- NOTCH signaling in Sertoli cells provides a negative feedback mechanism to control SSC proliferation and differentiation.
- Testicular stem/progenitor cells actively regulate their own niche environment through JAG1-mediated NOTCH activation.
- This JAG1-NOTCH-GDNF axis is critical for maintaining testicular homeostasis and regulating sperm output.
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