Oocytes are surrounded by somatic cells in the ovaries of newborn mammals. In rats, during the first 3 days after birth, the primordial follicles are assembled and remain developmentally arrested thereafter until the primary follicles are formed later [
1]. The primordial follicle growth signals the transition of the primordial follicle from quiescence to the next growth state—the primary follicle stage. As the process commences, the oocytes begin to grow and the granulosa cells around the oocyte become cubiform and proliferate rapidly. When the cubiform granulosa cells surrounding the growing oocytes reach more than one layer, the follicle become the secondary follicle [
2]. This progress requires a coordinated interaction of events, such as cell cycle progression, apoptosis, and differentiation of pluripotent somatic cells into the granulosa cell lineage. Although the exact factors and mechanisms that regulate folliculogenesis initiation remain elusive, the accumulated evidence suggests that the early growth stage of follicle development is not dependent on the gonadotropins but is mainly controlled by a combination of local paracrine factors within the ovaries. Some factors, such as stem cell factor (SCF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), leukemia inhibitory factor (LIF), nerve growth factor (NGF), bone morphogenic protein (BMP), growth differentiation factor 9 (GDF-9) and insulin-like growth factor (IGF), promote the development of the primordial follicles. Other factors, such as AMH, E
2 and P, inhibit primordial follicle development [
3‐
6]. Although we still poorly understand at the molecular level how these factors regulate primordial follicle development, successful activation of follicle growth must involve genetic networks both in germ and somatic cells. In recent years, genetic factors have received increasing attention as determinants of primordial follicle onset [
7‐
11]. In a recent study, we have showed that the mRNA of another Proto-oncogene,
c-erbB
2
, is expressed in the primordial follicle, and ablation of
c-erbB
2
in neonatal rat ovaries results in excessive inhibition of primordial follicles [
12], which demonstrates that
c-erbB
2
plays an important role in regulating primordial follicle onset. In addition to the evidence from our previous studies that
c-src mRNA is expressed in mammalian ovaries, primordial follicle growth was retarded and the number of mature follicles was significantly reduced in
c-src knock-out mice [
13,
14]. Based on this finding, it is tempting to speculate that
c-src might play an important role in regulating primordial follicle onset as well.
The proto-oncogene
c-src, an evolutionarily conserved proto-oncogene and the first carcinoma gene to be discovered in cells by Bioshop
et al. in 1976, is widely expressed in yeast, Drosophila and vertebrates, including humans.
c-src participates in the regulation of cell growth, development, differentiation and other biological functions. Src protein was the first member of the Src protein family kinases (SFKs) to be identified, and it is a non-receptor tyrosine protein kinase. During the oocyte maturation process, phosphorylated SFKs and non-phosphorylated SFKs are concentrated in the nucleus and the cortical region of the oocytes before germinal vesicle breakdown (GVBD). Once GVBD occurs, the activated SFK is distributed throughout the oocytes [
15‐
17]. These findings suggest that
c-src plays an important role in oocyte maturation. However, whether
c-src and Src protein are expressed during primordial follicle growth and what roles they play in this process have not been reported.
A variety of signaling pathways, including the MAPK and PKC pathways, are involved in the activation of the growth of primordial follicles [
18‐
21]. Signaling pathways, such as the PI3K and mTORC1 pathways, regulate the activation of primordial follicles and the early development of ovarian follicles [
7,
11]. It is possible that Src protein and the three intracellular signaling proteins (MAPK, PKC, PI3K) are inextricably linked. Both PKC isozymes and Fyn protein kinase exist in mammalian follicles, and PKC might induce the activation of eggs [
22,
23]. PP2, an inhibitor of Src protein, hindered the phosphorylation of PI3K and Akt [
24‐
26]. In this study, we will explore the possible signaling roles of
c-src in primordial follicle initiation in the context of other canonical signaling pathways.