Abstract
Backgroundc-erbB2, a proto-oncogene coding epidermal growth factor receptor-like receptor, also as a chemosensitivity/prognosis marker for gynecologic cancer, may be involved in initiation of growth of rat primordial follicles. The aim of the present study is to investigate the role and signal pathway of c-erbB2 in onset of rat primordial follicle development.MethodsThe expression of c-erbB2 mRNA and protein in neonatal ovaries cultured 4 and 8 days with/without epidermal growth factor (EGF) were examined by in situ hybridization, RT-PCR and western blot. The function of c-erbB2 in the primordial folliculogenesis was abolished by small interfering RNA transfection. Furthermore, MAPK inhibitor PD98059 and PKC inhibitor calphostin were used to explore the possible signaling pathway of c-erbB2 in primordial folliculogenesis.ResultsThe results showed that c-erbB2 mRNA was expressed in ooplasm and the expression of c-erbB2 decreased after transfection with c-erbB2 siRNA. Treatment with EGF at 50 ng/ml significantly increased c-erbB2 expression and primary and secondary follicle formation in ovaries. However, this augmenting effect was remarkably inhibited by c-erbB2 siRNA transfection. Furthermore, folliculogenesis offset was blocked by calphostin (5 × 10(-4) mmol/L) and PD98059 (5 × 10(-2) mmol/L), but both did not down-regulate c-erbB2 expression. In contrast, the expressions of p-ERK and p-PKC were decreased obviously by c-erbB2 siRNA transfection.Conclusionsc-erbB2 initiates rat primordial follicle growth via PKC and MAPK pathways, suggesting an important role of c-erbB2 in rat primordial follicle initiation and development.
Highlights
Folliculogenesis is a complex process consisting of sequential and ordered follicular development and growth
Expression of c-erbB2 in the ovaries during the initiation of growth of primordial follicle To examine the expression of c-erbB2, in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-polymerase chain reaction (PCR)) were performed
In conclusion, we showed that epidermal growth factor (EGF) promoted the initiation of primordial follicle development and the expression of c-erbB2 in ovaries, whereas the promoting effect of EGF was blocked by c-erbB2 siRNA transfection
Summary
Folliculogenesis is a complex process consisting of sequential and ordered follicular development and growth. Attention has focused on regulation of the initiation of follicular growth (follicle activation) [1,2]. The initiation of follicular growth and progression beyond the primary follicle stage requires locally produced factors and peptides, which can occur without gonadotrophins [3,4,5,6]. There is accumulating evidence implicating EGF as a key regulator of primordial follicle development in mammals. EGF triggered primordial follicle development by stimulating proliferation of granulosa cells [17]. The molecular mechanism by which EGF triggers primordial follicle development has not been fully clarified. The molecular mechanism by which EGF triggers primordial follicle development has not been fully clarified. c-erbB2, a member of the EGF receptor family, encoding a transmembrane EGF receptor [18,19], is expressed in primordial germ cells, granulosa cells, luteal cells and oocytes [20,21]. c-erbB2 is reported as a marker for chemosensitivity and prognosis of breast and ovarian cancer [22,23]
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