LKB1 acts as a critical gatekeeper of ovarian primordial follicle pool

Autor: Zong-Zhe Jiang, Xue-Shan Ma, Heide Schatten, Heng-Yu Fan, Qing-Yuan Sun, Zhen-Bo Wang, Meng-Wen Hu
Rok vydání: 2016
Předmět:
0301 basic medicine
AMP-activated kinase
Messenger
Reproductive health and childbirth
AMP-Activated Protein Kinases
Inbred C57BL
Immunoenzyme Techniques
Mice
Ovarian Follicle
Conditional gene knockout
2.1 Biological and endogenous factors
POF
Phosphorylation
Aetiology
skin and connective tissue diseases
Cells
Cultured
media_common
Cancer
Mice
Knockout
mTOR complex
Cultured
Blotting
Reverse Transcriptase Polymerase Chain Reaction
Polycystic ovary
Premature ovarian failure
medicine.anatomical_structure
liver kinase B1 (LKB1)
Oncology
Female
Folliculogenesis
Western
Research Paper
Signal Transduction
Infertility
medicine.medical_specialty
congenital
hereditary
and neonatal diseases and abnormalities
AMP-activated kinase (AMPK)
media_common.quotation_subject
Cells
Knockout
1.1 Normal biological development and functioning
Blotting
Western
Oncology and Carcinogenesis
Biology
Protein Serine-Threonine Kinases
Real-Time Polymerase Chain Reaction
03 medical and health sciences
Follicle
Underpinning research
Internal medicine
medicine
Genetics
Animals
Humans
RNA
Messenger
Ovarian follicle
Ovulation
Contraception/Reproduction
medicine.disease
liver kinase B1
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
mTOR complex (mTORC)
Oocytes
RNA
ovary
Zdroj: Oncotarget, vol 7, iss 5
Oncotarget
Popis: Liver Kinase b1 (LKB1/STK11)is a tumor suppressor responsible for the Peutz-Jeghers syndrome, an autosomal-dominant, cancer-prone disorder in which patients develop neoplasms in several organs, including the oviduct, ovary, and cervix. Besides, the C allele of a SNP in the Lkb1 gene impedes the likelihood of ovulation in polycystic ovary syndrome (PCOS) in women treated with metformin, a known LKB1-AMPK activator. It is very likely that LKB1 plays roles in female fertility. To identify the physiological functions of LKB1 in the mouse ovary, we selectively disrupted LKB1 in oocytes by the Cre-LoxP conditional knockout system and found that Lkb1fl/fl; Gdf9-Cre mice were severely subfertile with significantly enlarged ovaries compared to Lkb1fl/fl mice. Interestingly, without Lkb1 expression in oocytes from the primordial follicle stage, the entire primordial follicle pool was activated but failed to mature and ovulate, subsequently causing premature ovarian failure (POF). Further investigation demonstrated that elevated mTOR signaling regulated by an AKT-independent LKB1-AMPK pathway was responsible for the excessive follicle activation and growth. Our findings reveal the role of LKB1 as an indispensable gatekeeper for the primordial follicle pool, offer new functional understanding for the tumor suppressor genes in reproductive organs, and might also provide valuable information for understanding POF and infertility.
Databáze: OpenAIRE
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