Hypoxia inducible factor 2α/insulin-like growth factor receptor signal loop supports the proliferation and Oct-4 maintenance of mouse germline stem cells

Yen-Hua Huang, Mei-Hsiang Lin, P. C. Wang, Yu Chih Wu, H. L. Chiang, Y. L. Wang, Jui Hung Chang, Y. K. Huang, S. Y. Gu, Hong Nerng Ho, Thai Y. Ling

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10 引文 斯高帕斯(Scopus)

摘要

Hypoxia inducible factor 2α (HIF-2α) is critical for primordial germ cell (PGC) survival as knockout of HIF-2α (HIF-2α-/-) decreases both expression of Oct-4 and PGC number in genital ridge. Hypoxia is known to stabilize HIF-2α protein from proteasomal degradation. However, little is known about the hypoxia-associated endocrinal signaling in HIF-2α expression. The current work demonstrates a role for an endocrine insulin-like growth factor-I receptor (IGF-IR)-PI3K/Akt-mTOR-HIF-2α regulatory loop in the proliferation and Oct-4 maintenance of PGC-like alkaline phosphatase positive mouse germline stem cells (AP+GSCs).We found that hypoxia greatly increased the cell proliferation and the levels of nuclear Oct-4/HIF-2α protein of AP+ GSCs. The hypoxic-AP+ GSCs presented stronger stemness ability for germ cell differentiation than normoxic, with expressions of c-KIT (differentiation germ cell marker), VASA (differentiation germ cell marker) and SCP3 (meiotic marker) using a renal capsule transplantation assay. Meanwhile, hypoxia significantly increased the expression levels of secreted-IGF-I and IGF-IR. The IGF-I dose dependently increased the HIF-2α expression levels in AP+GSCs; and, the inhibition of IGF-IR byRNAinterference (shIGF-IR) or LY294002 (PI3K inhibitor)/Rapamycin (mTOR inhibitor) effectively suppressed the IGF-I- and/or hypoxia-induced HIF-2α and Oct-4 expression, suggesting that the IGF-IR and its downstream Akt/mTOR signaling are involved in the IGF-I/hypoxia effects. Additionally, knockdown of HIF-2αdramatically suppressed Oct-4 and IGF-IR protein levels inAP+GSCcells. In conclusion, the present study demonstrates a regulatory loop of IGF-IR-PI3K/Akt-mTOR-HIF-2α in proliferation and Oct-4 maintenance of PGC-like AP+GSCs under hypoxia. This finding provides insights into the niche endocrinology underlying early germ cell development.
原文英語
文章編號gau016
頁(從 - 到)526-537
頁數12
期刊Molecular Human Reproduction
20
發行號6
DOIs
出版狀態已發佈 - 2014

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Reproductive Medicine
  • Developmental Biology
  • Genetics
  • Cell Biology
  • Embryology
  • Molecular Biology
  • Medicine(all)

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