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Stepwise requirement of c-kit tyrosine kinase in mouse ovarian follicle development
H Yoshida1, N Takakura, H Kataoka
1Department of Molecular Genetics, Faculty of Medicine, Kyoto University, Sakyoku, Japan. hyoshida@virus.kyoto-u.ac.jp
Abstract:
Ovarian follicle development is controlled by the cycling variation of gonadotrophins derived from the central nervous system. Intragonadal signals are also required, especially in the autonomous development of small follicles. Receptor tyrosine kinase c-kit and its ligand SLF (Steel factor) are expressed on the surface of specific populations of follicle-forming cells in a contiguous manner and are thought to have important roles in follicular development. We blocked the interaction of c-kit and its ligand by administering the function-blocking antibody ACK2 to developing mice at various times after birth and monitored ovarian follicle development. A blockade of c-kit function disturbed the onset of primordial follicle development, primary follicle growth, follicular fluid formation of preantral follicles, and penultimate-stage ovarian follicle maturation before ovulation. Ovarian follicle growth was dependent on c-kit during the first 5 days after birth when the functional FSH receptor is not yet expressed in mouse ovary. In contrast, primordial follicle formation and survival, small preantral or antral follicle development, ovulation, and luteinization of the ovulated follicle were not affected by this antibody. These findings indicate the stepwise requirement of c-kit and its ligand interaction system in the developing ovarian follicle and that c-kit with its ligand supports the autonomous development of ovarian follicle independent of gonadotrophins.
Insights
The c-kit signaling pathway is crucial for early ovarian follicle development in mice, supporting growth before gonadotropin receptors are active. This pathway regulates key stages of follicle maturation, independent of central nervous system control.
Area of Science:
- Reproductive Biology
- Developmental Biology
- Cell Signaling
Background:
- Ovarian follicle development relies on both central gonadotropins and local intragonadal signals.
- The c-kit receptor tyrosine kinase and its ligand, Steel factor (SLF), are expressed in ovarian cells and implicated in follicular growth.
- The precise role of c-kit signaling in the stepwise development of ovarian follicles remains to be fully elucidated.
Purpose of the Study:
- To investigate the specific roles of the c-kit/SLF signaling pathway in ovarian follicle development in mice.
- To determine the dependency of different follicular developmental stages on c-kit function.
- To assess whether c-kit signaling is required for gonadotropin-independent follicle development.
Main Methods:
- Administration of the function-blocking antibody ACK2 to mice during postnatal development to inhibit c-kit signaling.
- Monitoring and analysis of ovarian follicle development at various stages.
- Assessment of specific developmental milestones including primordial follicle initiation, growth, and maturation.
Main Results:
- Blocking c-kit function disrupted primordial follicle initiation, primary follicle growth, and preantral follicle maturation.
- Ovarian follicle growth was dependent on c-kit signaling during the first five postnatal days, preceding FSH receptor expression.
- Primordial follicle survival, later follicular development, ovulation, and luteinization were unaffected by c-kit blockade.
Conclusions:
- The c-kit/SLF system plays a critical, stepwise role in the early, autonomous development of ovarian follicles.
- C-kit signaling is essential for initiating and promoting the growth of small ovarian follicles, independent of gonadotropins.
- This pathway is vital for specific stages of follicle maturation before the onset of gonadotropin receptor function.