Abstract
In mammals, female fecundity is determined by the size of the primordial follicle (PF) pool, which is established during the perinatal period. As a non-renewable resource, the preservation of dormant PFs is crucial for sustaining female reproduction throughout life. Although studies have revealed that several oocyte-derived functional genes and pathways, such as newborn ovary homeobox (NOBOX) and 3-phosphoinositide-dependent protein kinase-1, participate in maintaining the PF pool, our understanding of the underlying molecular mechanisms is still incomplete. Here, we demonstrate that E-cadherin (E-cad) plays a crucial role in the maintenance of PFs in mice. E-cad is specifically localized to the cytomembrane of oocytes in PFs. Knockdown of E-cad in neonatal ovaries resulted in significant PF loss owing to oocyte apoptosis. In addition, the expression pattern of NOBOX is similar to that of E-cad. Knockdown of E-cad resulted in a decreased NOBOX level, whereas overexpression of Nobox partially rescued the follicle loss induced by silencing E-cad. Furthermore, E-cad governed NOBOX expression by regulating the shuttle protein, β-catenin, which acts as a transcriptional co-activator. Notably, E-cad, which is a transmembrane protein expressed in the oocytes, was also responsible for maintaining the PF structure by facilitating cell–cell adhesive contacts with surrounding pregranulosa cells. In conclusion, E-cad in oocytes of PFs plays an indispensable role in the maintenance of the PF pool by facilitating follicular structural stability and regulating NOBOX expression. These findings shed light on the physiology of sustaining female reproduction.
Highlights
Ovarian follicles serve as the basic and non-renewable reproductive unit of female mammals[1]
Because primordial follicle (PF) are the non-renewable source of fertilizable ova, the survival of PFs is important for the female reproductive lifespan
We demonstrated that E-cad has an important role in sustaining PF survival in neonatal mouse ovaries, which is achieved by regulating newborn ovary homeobox (NOBOX) expression in oocytes and sustaining cell–cell adhesion between germ cells and PF granulosa cells
Summary
Ovarian follicles serve as the basic and non-renewable reproductive unit of female mammals[1]. Oocyte-derived molecules are pivotal for the survival of PFs after birth. 3-phosphoinositide-dependent protein kinase-1, the upstream molecule of protein kinase B (AKT), preserves the reproductive lifespan by maintaining the survival of ovarian PFs8. The phosphatidylinositol 3-kinase (PI3K) and mTORC1 pathways control PF activation and their activators have been applied in the in vitro activation of PFs in the clinic to treat premature ovarian insufficiency (POI), which is generally characterized by amenorrhea before the age of 40 years[2,4,10,11,12]. The role of above molecules and pathways in controlling the preservation of PFs has been revealed, the detailed mechanism needs further study to better understand the etiology of POI
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