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WIREs Dev Biol
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Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle

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Prior to ovulation, the mammalian oocyte undergoes a process of differentiation within the ovarian follicle that confers on it the ability to give rise to an embryo. Differentiation comprises two phases—growth, during which the oocyte increases more than 100‐fold in volume as it accumulates macromolecules and organelles that will sustain early embryogenesis; and meiotic maturation, during which the oocyte executes the first meiotic division and prepares for the second division. Entry of an oocyte into the growth phase appears to be triggered when the adjacent granulosa cells produce specific growth factors. As the oocyte grows, it elaborates a thick extracellular coat termed the zona pellucida. Nonetheless, cytoplasmic extensions of the adjacent granulosa cells, termed transzonal projections (TZPs), enable them to maintain contact‐dependent communication with the oocyte. Through gap junctions located where the TZP tips meet the oocyte membrane, they provide the oocyte with products that sustain its metabolic activity and signals that regulate its differentiation. Conversely, the oocyte secretes diffusible growth factors that regulate proliferation and differentiation of the granulosa cells. Gap junction‐permeable products of the granulosa cells prevent precocious initiation of meiotic maturation, and the gap junctions also enable oocyte maturation to begin in response to hormonal signals received by the granulosa cells. Development of the oocyte or the somatic compartment may also be regulated by extracellular vesicles newly identified in follicular fluid and at TZP tips, which could mediate intercellular transfer of macromolecules. Oocyte differentiation thus depends on continuous signaling interactions with the somatic cells of the follicle.

Postnatal oocyte and follicular development. (a) The arrangement of the principal cell types of the follicle at different stages of oocyte and follicular growth is shown. Each primordial follicle contains one oocyte enclosed by a small number of squamous granulosa cells. The first morphological sign that a follicle and its oocyte have entered the growth phase is a transition of the granulosa from a squamous to cuboidal morphology. As the oocyte grows, the cuboidal granulosa cells proliferate so that they continue to cover the surface of the oocyte. Continued proliferation of the granulosa cells generates a second layer, defining the follicle as secondary. Thecal cells are recruited around the exterior of the follicle and are separated from the granulosa cells by a basement membrane. As the follicle continues to grow, a fluid‐filled cavity termed the antrum appears. This divides the granulosa into mural and cumulus subpopulations, which express different genes and follow different fates. Even though the follicle will continue to increase in size, growth of the oocyte slows or stops at the antral stage. This transition is accompanied by transcriptional arrest and a change in the degree of condensation and spatial arrangement of the DNA in the oocyte nucleus, from a nonsurrounded nucleolus (NSN) to a surrounded nucleolus (SN) configuration, as shown in the oocyte in the preovulatory follicle. The fully grown oocyte contains, in addition to actively translated mRNAs, products including stored translationally inactive mRNAs and mitochondria that are required during meiotic maturation or early embryogenesis. (b) The nuclear events of meiotic maturation are highlighted. The membrane surrounding the nucleus (germinal vesicle) breaks down and the chromosomes condense and align on the spindle, which becomes translocated to the periphery of the oocytes. The first meiotic division segregates homologous chromosomes and one set is discarded in the first polar body. The chromosomes remaining in the oocyte then align on a second spindle. Meiosis becomes arrested at metaphase II until fertilization activates the egg. During maturation, the cumulus granulosa cells secrete a matrix that separates them from each other and from the oocyte and physical contact between the two cell types is terminated. (Modified with permission from Ref . Copyright 2016 Springer International)
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New mechanisms of intrafollicular communication: extracellular vesicles (EVs). EVs are present in follicular fluid and represent a potential mechanism by which macromolecules including mRNA and miRNA could be transferred between cells. Structures resembling EV have also been detected at the tips of transzonal projections (TZPs) and could permit similar transfer from cumulus granulosa cells to the oocyte. (Modified with permission from Ref . Copyright 2017 Springer International)
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Regulation of meiotic maturation. (a) Before the activation of the luteinizing hormone (LH) receptor (LHCGR), the mural granulosa cells produce and release NPPC, which activates its receptor, NPR2, located on both mural and cumulus granulosa cells. Active NPR2 generates cGMP, which diffuses through gap junctions and reaches a concentration in the oocyte that is sufficient to inhibit phosphodiesterase 3A (PDE3A). This allows the concentration of cAMP, produced by the oocyte, to remain high thereby maintaining CDK1 in a hyper‐phosphorylated inactive form. (b) Binding of LH to LHCGR triggers the release of ligands from the mural granulosa cells that activate EGFR on the mural and cumulus granulosa cells. cGMP levels within the granulosa cells fall due both to inhibition of its synthesis owing to dephosphorylation of NPR2 and (later) reduced production of NPPC and to increased hydrolysis owing to activation by phosphorylation of PDE5A in the granulosa cells. The relative contribution of LHCGR‐ and EGFR‐mediated signaling to these events remains to be fully elucidated. As the concentration of cGMP within the granulosa cells falls, it flows out of the oocyte to equalize its concentration throughout the granulosa cell–oocyte compartment. The decreased cGMP in the oocyte permits PDE3A to become active and hydrolyze cAMP, enabling dephosphorylation and activation of CDK1. (Modified with permission from Ref . Copyright 2016 Springer International)
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Communication between the growing oocyte and adjacent granulosa cells. (a) Gap junctions enable the granulosa cells to transfer pyruvate, nucleotides, and amino acids to the oocyte. The granulosa cells also provide the oocyte with cholesterol, which might be transferred between cells where the plasma membranes lie in close apposition. It is unknown whether the oocyte supplies essential factors to the granulosa cells via gap junctions. (b) Granulosa cells produce Kit ligand (KITL) whereas oocytes express the KIT membrane receptor. The membrane‐associated form of KITL promotes oocyte growth more efficiently than soluble KITL. Oocytes secrete the transforming growth factor (TGFβ) family members, GDF9 and BMP15, as well as FGF8B, which activate receptors on the granulosa cell plasma membranes.
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Transzonal projections (TZPs). (a) A dense forest of TZPs, indicated by the arrow, projects from the cumulus granulosa cells to the oocyte. Phalloidin (green) stains their actin‐rich cytoskeleton as well as the cortex of the oocyte. Nuclei are stained using DAPI (blue). Bar = 25 µm. (b) Higher‐power magnification shows that several TZPs often appear to emerge from a single locus (arrows). (c) Electron‐micrograph showing an oocyte at an early stage of growth, as indicated by the thin zona pellucida (zp), and an incipient TZP (arrow) projecting from a granulosa cell. Bar = 500 nm. (d) Electron‐micrograph showing an oocyte at a later stage of growth and several narrow and elongated TZPs (one marked by arrow). Bar = 500 nm. (e) Cartoon depicting interactions between TZP tips and oocyte plasma membrane. The TZPs are anchored by adherens and possibly other types of junctions. Gap junctions permit the passage of molecules up to 1 kDa. The TZP–oocyte interface is presumably also the site of contact between membrane‐associated growth factors and their membrane‐associated receptors. (f) Two nonexclusive models of how TZPs may form: Stretching model (upper panel). (1) Prior to deposition of the zona pellucida, the plasma membranes of the oocyte (pink) and adjacent granulosa cells (light brown) are in physical contact at numerous sites (two shown here per granulosa for simplicity). (2) Deposition of the zona pellucida (light blue) pushes the bodies of the granulosa cells away from the oocyte, but the cells remain connected at the original points of contact. (3) As the oocyte continues to grow and the zona pellucida thickens, the cytoplasmic strands of the granulosa cell elongate to produce TZPs. New granulosa cells (dark brown) are born to enable a continuous layer to be maintained around the expanding oocyte surface. (4) Because granulosa cells born after the deposition of the zona pellucida have never been in direct contact with the oocyte, they do not generate TZPs. Hence, the number of TZPs does not increase as oocytes grow. Pushing model (lower panel). (1, 2) Deposition of the zona pellucida prevents physical contact of the oocyte and surrounding granulosa cells. (3) Granulosa cells elaborate filopodia‐like structures that extend towards the oocyte. New granulosa cells (dark brown) are generated as the oocyte surface expands. (4) The newborn granulosa cells elaborate new TZPs. Hence, the number of TZPs increases as oocytes grow.
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Initiation of oocyte and follicular growth. (a) Schematic representation of the canonical phosphatidylinositide 3‐kinase (PI3‐kinase) signaling pathway. (b) Possible signaling pathway that activates oocyte growth. Oocytes in primordial follicles are enclosed by squamous granulosa cells. Unknown signals trigger an increase in protein synthesis in the granulosa cells and a transition to a cuboidal morphology. This may reflect entry into the mitotic cell cycle. The granulosa cells may increase production of Kit ligand (KITL); another possibility is that synthesis of the more bioactive membrane‐bound form becomes favored. The consequent activation of KIT signaling within the oocyte increases protein synthesis, thus driving an increase in cell size.
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