β-catenin regulates GnRH-induced FSHβ gene expression

Area of Science:

• Reproductive biology
• Molecular endocrinology
• Cell signaling

Background:

• Gonadotropin synthesis is crucial for reproduction and regulated by GnRH.
• β-catenin is known to be involved in LHβ induction by GnRH.
• The precise role of β-catenin in FSHβ gene expression requires further elucidation.

Purpose of the Study:

• To investigate the role of β-catenin in FSHβ gene expression in LβT2 gonadotrope cells.
• To identify the signaling pathways and molecular mechanisms through which β-catenin regulates FSHβ.
• To explore potential cofactors involved in β-catenin-mediated FSHβ induction.

Main Methods:

• Utilized LβT2 gonadotrope cells for experiments.
• Employed small interfering RNA (siRNA) for β-catenin knockdown.
• Conducted luciferase reporter assays with FSHβ promoter constructs.
• Performed chromatin immunoprecipitation (ChIP) and RNA sequencing.
• Investigated the role of breast cancer metastasis-suppressor 1-like (Brms1L).

Main Results:

• GnRH increased nuclear β-catenin levels, dependent on β-catenin for FSHβ mRNA induction.
• β-catenin regulation of FSHβ was independent of the JNK-c-jun pathway and did not affect mRNA stability.
• GnRH responsiveness was linked to the proximal FSHβ promoter but not specific TCF/LEF binding sites.
• RNA sequencing identified Brms1L as a downstream target of β-catenin.
• Knockdown of Brms1L attenuated GnRH-induced FSHβ expression.

Conclusions:

• β-catenin is essential for GnRH-induced FSHβ gene expression in gonadotropes.
• The mechanism involves the nuclear cofactor Brms1L, which is regulated by β-catenin.
• This pathway contributes to the neuroendocrine control of reproduction, distinct from the JNK-c-jun pathway.