AKT3 Is a Pivotal Molecule of Cadherin‐22 and GDNF Family Receptor‐α1 Signal Pathways Regulating Self‐Renewal in Female Germline Stem Cells

Female germline stem cells (FGSCs) are rare population residing in cortex of ovary, with the potential to rescue female infertility caused by ovary failure. Recently, we reported that cadherin‐22 (CDH22), a member of cadherin family, regulates self‐renewal of mouse FGSCs via interaction with JAK‐STAT signal pathway and β‐catenin. In this study, the expression profiles of FGSCs and spermatogonial stem cells (SSCs) were analyzed to further reveal their similarity and difference, and AKT3 was predicted as a pivotal molecule for FGSCs self‐renewal. Then, we demonstrated that CDH22 interacted with PI3K to phosphorylate AKT3 and subsequently enhanced the expression levels of N‐myc and cyclin family in FGSCs to promote self‐renewal. Moreover, glial cell line‐derived neurotrophic factor (GDNF) was identified as an essential factor for FGSCs self‐renewal with a more complicated mechanism: GDNF‐GFRA1 activates AKT3 via PI3K or Src family kinase (SFK), and SFK upregulates its target genes, Bcl6b, Etv5, and Lhx1, to promote self‐renewal of FGSCs. However, Src, the key intermediate factor for SSCs, was not the functional molecule of SFK family in the GDNF signal network of FGSCs. Based on the observations of bioinformatics analysis and molecular evidence, we demonstrate the underlying links of potential factors which are critical to the self‐renewal in FGSC and imply the therapeutic potentials of FGSCs in cure of female infertility. Stem Cells 2019;37:1095–1107 The schematic illustration of cadherin‐22 and GDNF signal network in female germline stem cells.