In vertebrate species that ovulate one or a limited number of ovarian follicles per reproductive cycle, the cellular processes by which follicle selection (cyclic recruitment) is mediated and final differentiation is initiated remain largely unknown. In the hen ovary, the selection of a single follicle into the preovulatory hierarchy on an approximate daily basis occurs from a small cohort of prehierarchal follicles measuring approximately 6- to 8-mm in diameter. Given that the granulosa layer undergoes a dramatic alteration in phenotype subsequent to follicle selection, of particular interest are the cell signaling and associated transcriptional mechanisms that regulate this transition. Recent studies suggest that granulosa cells from prehierarchal follicles are normally maintained in an undifferentiated state by inhibitory MAP kinase (MAPK) signaling mediated by epidermal growth factor receptor ligands (EGFRLs). One of the earliest markers for differentiating granulosa cells is elevated expression of FSH receptor (fshr) mRNA and enhanced FSH-induced cyclic adenosine monophosphate (cAMP) production. EGFRL/MAPK signaling is proposed to inhibit fshr transcription via its ability to induce Inhibitor of differentiation/DNA binding (Id) protein isoforms, Id1, Id3 and Id4. Subsequent to follicle selection, cAMP-induced Id2 expression is considered both sufficient and necessary for fshr transcription. Two working models are proposed which predict that enhanced FSHR expression and the progression of granulosa cell differentiation occurs as a result of a decline in MAPK signaling from within granulosa cells (internal model for differentiation) and/or elevated cAMP signaling promoted by an endocrine, neuroendocrine or neuronal factor (external model).
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