Background In a growth phase occurring during most of folliculogenesis, the oocyte produces and accumulates molecules and organelles that are fundamental for the development of the preimplantation embryo. At ovulation, growth is followed by a phase of maturation that, although confined within a short temporal window, encompasses modifications of the oocyte chromosome complement and rearrangements of cytoplasmic components that are crucial for the achievement of developmental competence. Cumulus cells (CCs) are central to the process of maturation, providing the oocyte with metabolic support and regulatory cues. Methods PubMed was used to search the MEDLINE database for peer-reviewed original articles and reviews concerning oocyte maturation in mammals. Searches were performed adopting 'oocyte' and 'maturation' as main terms, in association with other keywords expressing concepts relevant to the subject. The most relevant publications, i.e. those concerning major phenomena occurring during oocyte maturation in established experimental models and the human species, were assessed and discussed critically to offer a comprehensive description of the process of oocyte maturation. Results By applying the above described search criteria, 6165 publications were identified, of which 543 were review articles. The number of publications increased steadily from 1974 (n = 7) to 2013 (n = 293). In 2014, from January to the time of submission of this manuscript, 140 original manuscripts and reviews were published. The studies selected for this review extend previous knowledge and shed new and astounding knowledge on oocyte maturation. It has long been known that resumption of meiosis and progression to the metaphase II stage is intrinsic to oocyte maturation, but novel findings have revealed that specific chromatin configurations are indicative of a propensity of the oocyte to resume the meiotic process and acquire developmental competence. Recently, genetic integrity has also been characterized as a factor with important implications for oocyte maturation and quality. Changes occurring in the cytoplasmic compartment are equally fundamental. Microtubules, actin filaments and chromatin not only interact to finalize chromosome segregation, but also crucially co-operate to establish cell asymmetry. This allows polar body extrusion to be accomplished with minimal loss of cytoplasm. The cytoskeleton also orchestrates the rearrangement of organelles in preparation for fertilization. For example, during maturation the distribution of the endoplasmic reticulum undergoes major modifications guided by microtubules and microfilaments to make the oocyte more competent in the generation of intracellular Ca(2+) oscillations that are pivotal for triggering egg activation. Cumulus cells are inherent to the process of oocyte maturation, emitting regulatory signals via direct cell-to-cell contacts and paracrine factors. In addition to nurturing the oocyte with key metabolites, CCs regulate meiotic resumption and modulate the function of the oocyte cytoskeleton. Conclusions Although the importance of oocyte maturation for the achievement of female meiosis has long been recognized, until recently much less was known of the significance of this process in relation to other fundamental developmental events. Studies on chromatin dynamics and integrity have extended our understanding of female meiosis. Concomitantly, cytoskeletal and organelle changes and the ancillary role of CCs have been better appreciated. This is expected to inspire novel concepts and advances in assisted reproduction technologies, such as the development of novel in vitro maturation systems and the identification of biomarkers of oocyte quality.

Oocyte maturation: gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization

Female fertility is determined to a large extent by the quality (developmental competence) of the oocyte as reflected in its ability to undergo meiosis, be fertilized, and give rise to a healthy embryo. Growth of the mammalian oocyte is coordinated with that of the follicle that encloses it by the actions of signals that pass in both directions between the germline and somatic components. This review summarizes what is known about the roles played by 2 different modes of intrafollicular signalling in oogenesis: paracrine factors activating receptors on the opposite cell type, and direct sharing of small molecules throughout the follicle via gap junction channels. Recent evidence indicates that these 2 modes of signalling interact to regulate oocyte growth and granulosa cell proliferation and that defects in either can contribute to female infertility.

Bidirectional communication between oocytes and follicle cells: ensuring oocyte developmental competence.

https://ircms.kumamoto-u.ac.jp/research/guojun_sheng/docs/cancerletters.pdf

EMT in developmental morphogenesis

Abnormalities in ovarian function, including defective oogenesis and folliculogenesis, represent a key female reproductive deficiency. Accumulating evidence in the literature has shown that the PI3K/PTEN/Akt and TSC/mTOR signaling pathways are critical regulators of ovarian function including quiescence, activation, and survival of primordial follicles, granulosa cell proliferation and differentiation, and meiotic maturation of oocytes. Dysregulation of these signaling pathways may contribute to infertility caused by impaired follicular development, intrafollicular oocyte development, and ovulation. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/Akt and TSC/mTOR pathways during mammalian oogenesis and folliculogenesis and their association with female infertility.

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PI3K/PTEN/Akt and TSC/mTOR signaling pathways, ovarian dysfunction, and infertility: an update.

Follicle classification is an important aid to the understanding of follicular development and atresia. Some bovine primordial follicles have the classical primordial shape, but ellipsoidal shaped follicles with some cuboidal granulosa cells at the poles are far more common. Preantral follicles have one of two basal lamina phenotypes, either a single aligned layer or one with additional layers. In antral follicles 5 mm, only aligned/rounded phenotypes are present. Dominant and subordinate follicles can be identified by ultrasound and/or histological examination of pairs of ovaries. Atretic follicles 5 mm, only antral atresia is observed. The concentrations of follicular fluid steroid hormones can be used to classify atresia and distinguish some of the different types of atresia; however, this method is unlikely to identify follicles early in atresia, and hence misclassify them as healthy. Other biochemical and histological methods can be used, but since cell death is a part of normal homoeostatis, deciding when a follicle has entered atresia remains somewhat subjective.

/pdf/morphological-classification-of-bovine-ovarian-follicles-4fxg530vmw.pdf

Morphological classification of bovine ovarian follicles.

In the ovary, initiation of follicle growth is marked by cuboidalization of flattened granulosa cells (GCs) The regulation and cell biology of this shape change remains poorly understood We propose that characterization of intercellular junctions and associated proteins is key to identifying as yet unknown regulators of this important transition As GCs are conventionally described as epithelial cells, this study used mouse ovaries and isolated follicles to investigate epithelial junctional complexes (tight junctions [TJ], adherens junctions [AJ], and desmosomes) and associated molecules, as well as classic epithelial markers, by quantitative PCR and immunofluorescence These junctions were further characterized using ultrastructural, calcium depletion and biotin tracer studies Junctions observed by transmission electron microscopy between GCs and between GCs and oocyte were identified as AJs by expression of N-cadherin and nectin 2 and by the lack of TJ and desmosome-associated proteins Follicles were also permeable to biotin, confirming a lack of functional TJs Surprisingly, GCs lacked all epithelial markers analyzed, including Ecadherin, cytokeratin 8, and zonula occludens (ZO)-1alpha+ Furthermore, vimentin was expressed by GCs, suggesting a more mesenchymal phenotype Under calcium-free conditions, small follicles maintained oocyte-GC contact, confirming the importance of calcium-independent nectin at this stage However, in primary and multilayered follicles, lack of calcium resulted in loss of contact between GCs and oocyte, showing that nectin alone cannot maintain attachment between these two cell types Lack of classic markers suggests that GCs are not epithelial Identification of AJs during GC cuboidalization highlights the importance of AJs in regulating initiation of follicle growth adhesion, cell shape, follicle, junctions, ovary

Characterization and Significance of Adhesion and Junction-Related Proteins in Mouse Ovarian Follicles

The postnatal mouse ovary is rich in quiescent and early-growing oocytes, each one surrounded by a layer of somatic granulosa cells (GCs) on a basal lamina. As oocytes start to grow the GCs change shape from flattened to cuboidal, increase their proliferation and form multiple layers, providing a unique model for studying the relationship between cell shape, proliferation and multilayering within the context of two different intercommunicating cell types: somatic and germ cells. Proliferation of GCs was quantified using immunohistochemistry for Ki67 and demonstrated that, unusually, cuboidal cells divided more than flat cells. As a second layer of GCs started to appear, cells on the basal lamina reached maximum packing density and the axes of their mitoses became perpendicular to the basal lamina, resulting in cells dividing inwards to form second and subsequent layers. Proliferation of basal GCs was less than that of inner cells. Ultrastructurally, collagen fibrils outside the basal lamina became more numerous as follicles developed. We propose that the basement membrane and/or theca cells that surround the follicle provide an important confinement for rapidly dividing columnar cells so that they attain maximum packing density, which restricts lateral mitosis and promotes inwardly oriented cell divisions and subsequent multilayering.

/pdf/effect-of-cell-shape-and-packing-density-on-granulosa-cell-1jqe85spe7.pdf

Effect of cell shape and packing density on granulosa cell proliferation and formation of multiple layers during early follicle development in the ovary.

1. 1. Da Silva-Buttkus P., 2. et al.
 2008. J. Cell Sci. doi:10.1242/jcs.036400
 [OpenUrl][1][Abstract/FREE Full Text][2]

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Effect of cell shape and packing density on granulosa cell proliferation and formation of multiple layers during early follicle development in the ovary

Marianne Baithun

Papers

Characterization and Significance of Adhesion and Junction-Related Proteins in Mouse Ovarian Follicles

Effect of cell shape and packing density on granulosa cell proliferation and formation of multiple layers during early follicle development in the ovary.

Effect of cell shape and packing density on granulosa cell proliferation and formation of multiple layers during early follicle development in the ovary