Follicle loss and PTEN/PI3K/mTOR signaling pathway activated in LepR-mutated mice

Area of Science:

• Reproductive Biology
• Molecular Endocrinology
• Genetics

Background:

• The leptin receptor (LepR) plays a crucial role in regulating female reproduction.
• Specific tyrosine residues in LepR are critical for its signaling function.
• Mutations in LepR can lead to reproductive abnormalities.

Purpose of the Study:

• To investigate the reproductive alterations in female mice with a specific LepR mutation (Y123F).
• To elucidate the underlying molecular mechanisms, focusing on downstream signaling pathways in the ovaries.

Main Methods:

• Generated female mice (Y123F) with homologous gene targeting, replacing key tyrosine residues in LepR with phenylalanine.
• Compared reproductive characteristics and ovarian gene expression between homozygous Y123F mice and wild-type littermates.
• Analyzed the phosphorylation status of key molecules in the Akt/mTOR, PTEN, and IRS pathways within the ovaries.

Main Results:

• Y123F homozygous female mice exhibited complete infertility with no reproductive cycles.
• These mice showed decreased anti-Mullerian hormone (AMH) levels and significant reductions in all ovarian follicle types.
• Ovarian analysis revealed elevated phosphorylation of Akt, mTOR, S6K1, and eIF4B, alongside decreased IRS-1/2 and PTEN phosphorylation, and increased FOXO-3A phosphorylation.

Conclusions:

• LepR mutation (Y123F) in female mice leads to substantial follicle loss and ovarian dysfunction.
• The mutation activates the PTEN/PI3K/Akt/mTOR signaling pathway in the ovaries.
• This reproductive impairment occurs independently of the canonical insulin signaling pathway.