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Loss of Frmd5 Inhibits Jak2-Stat3 Signalling Pathway and Impairs Cell Apoptosis During Vagina Luminal Formation in
Tiantian Su1,2, Zhenbin Wang1, Yunjiao Wu1
1Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences; Peking University International Cancer Institute; Peking University Health Science Center, 100191 Beijing, China.
Abstract:
FRMD5, FERM-domain protein 5, has been reported to be associated with tumors progession and neurodevelopment, however its molecular mechanisms in normal cells and its functions during urinary epithelium development remain unknown. In this study, we identified that Frmd5 interacts with Jak2 and Stat3, leading to the enhanced Jak2/Stat3 complex formation and subsquently promoting phosphorylation of Stat3. In a urinary epithelium specific knockout of Frmd5 mouse, Jak2-Stat3 signaling pathway was significantly inactivated and apoptosis of epithelium was significantly downregulated compared with Cdh16-Cre-; Frmd5flox/flox control mouse. In Cdh16-Cre+; Frmd5flox/flox vaginal epithelium pro-apoptotic genes (Casp3, Casp8) was decreased and anti-apoptotic genes (Bcl2, Bcl-XL) was increased compared with Cdh16-Cre-; Frmd5flox/flox vaginal epithelium. A total of 56.7% Cdh16-Cre+; Frmd5flox/flox mice failed to form vaginal lumen and developed longitudinal vaginal septum coupled with infertility in these mice. In summary, we demonstrated that Frmd5 is essential for activation of Jak2-Stat3 signaling pathway and is required for vaginal lumen development in mice.
Insights
FERM-domain protein 5 (Frmd5) is crucial for vaginal lumen development in mice. It activates the Jak2-Stat3 signaling pathway, essential for normal urinary epithelium formation and preventing infertility.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Mechanisms
Background:
- FERM-domain protein 5 (Frmd5) is implicated in tumor progression and neurodevelopment.
- Its role in normal cellular functions and urinary epithelium development is largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms of Frmd5 in normal cells.
- To investigate the function of Frmd5 during urinary epithelium development.
Main Methods:
- Investigated Frmd5 interaction with Jak2 and Stat3.
- Utilized a urinary epithelium-specific Frmd5 knockout mouse model (Cdh16-Cre+; Frmd5flox/flox).
- Analyzed gene expression of apoptotic and anti-apoptotic markers.
Main Results:
- Frmd5 interacts with Jak2 and Stat3, enhancing complex formation and Stat3 phosphorylation.
- Knockout of Frmd5 inactivated the Jak2-Stat3 pathway and reduced epithelial apoptosis.
- Frmd5 deficiency led to decreased pro-apoptotic genes (Casp3, Casp8) and increased anti-apoptotic genes (Bcl2, Bcl-XL).
- 56.7% of knockout mice failed to form vaginal lumens, exhibiting vaginal septum and infertility.
Conclusions:
- Frmd5 is essential for activating the Jak2-Stat3 signaling pathway.
- Frmd5 plays a critical role in vaginal lumen development in mice.
- Dysregulation of Frmd5 impacts epithelial apoptosis and reproductive tract formation.
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