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Open accessJournal ArticleDOI: 10.1038/S41467-021-21644-Z

Epidermal growth factor receptor signaling uncouples germ cells from the somatic follicular compartment at ovulation.

04 Mar 2021-Nature Communications (Springer Science and Business Media LLC)-Vol. 12, Iss: 1, pp 1438-1438
Abstract: Germ cells are physically coupled to somatic support cells of the gonad during differentiation, but this coupling must be disrupted when they are mature, freeing them to participate in fertilization. In mammalian females, coupling occurs via specialized filopodia that project from the ovarian follicular granulosa cells to the oocyte. Here, we show that signaling through the epidermal growth factor receptor (EGFR) in the granulosa, which becomes activated at ovulation, uncouples the germ and somatic cells by triggering a massive and temporally synchronized retraction of the filopodia. Although EGFR signaling triggers meiotic maturation of the oocyte, filopodial retraction is independent of the germ cell state, being regulated solely within the somatic compartment, where it requires ERK-dependent calpain-mediated loss of filopodia-oocyte adhesion followed by Arp2/3-mediated filopodial shortening. By uncovering the mechanism regulating germ-soma uncoupling at ovulation, our results open a path to improving oocyte quality in human and animal reproduction.

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Topics: Germ cell (61%), Oocyte (58%), Somatic cell (57%) ... read more
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5 results found


Open accessJournal ArticleDOI: 10.1007/S12551-021-00891-W
Marcos Roberto Chiaratti1Institutions (1)
Abstract: Oocyte health is tightly tied to mitochondria given their role in energy production, metabolite supply, calcium (Ca2+) buffering, and cell death regulation, among others. In turn, mitochondrial function strongly relies on these organelle dynamics once cyclic events of fusion and fission (division) are required for mitochondrial turnover, positioning, content homogenization, metabolic flexibility, interaction with subcellular compartments, etc. Importantly, during oogenesis, mitochondria change their architecture from an “orthodox” elongated shape characterized by the presence of numerous transversely oriented cristae to a round-to-oval morphology containing arched and concentrically arranged cristae. This, along with evidence showing that mitochondrial function is kept quiescent during most part of oocyte development, suggests an important role of mitochondrial dynamics in oogenesis. To investigate this, recent works have downregulated/upregulated in oocytes the expression of key effectors of mitochondrial dynamics, including mitofusins 1 (MFN1) and 2 (MFN2) and the dynamin-related protein 1 (DRP1). As a result, both MFN1 and DRP1 were found to be essential to oogenesis and fertility, while MFN2 deletion led to offspring with increased weight gain and glucose intolerance. Curiously, neither MFN1/MFN2 deficiency nor DRP1 overexpression enhanced mitochondrial fragmentation, indicating that mitochondrial size is strictly regulated in oocytes. Therefore, the present work seeks to discuss the role of mitochondria in supporting oogenesis as well as recent findings connecting defective mitochondrial dynamics in oocytes with infertility and transmission of metabolic disorders.

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Topics: MFN2 (65%), Mitochondrial Turnover (65%), Mitochondrial Size (63%) ... read more

1 Citations


Open accessJournal ArticleDOI: 10.1071/RD21282
Claude Robert1Institutions (1)
Abstract: The determinants of oocyte quality remain uncertain. Under suitable conditions, which have yet to be defined, the gamete grows and acquires the competence to resume meiosis, be fertilised and undergo embryonic development at least beyond genome activation, after which the blastomere is autonomous enough to adapt to the specificity of its environment. This review describes the central role played by the oocyte in reproductive success and how communication between cumulus cells and the oocyte are essential to proper oogenesis and the quality of the resulting gamete. While most attempts to improve oocyte quality have been directed at gonadotrophin-based systemic endocrine signalling, it is proposed that parallel control of fertility may act locally within ovarian follicles through intimate cooperation between somatic cells and the oocyte via the network of transzonal projections. This intercellular communication may prove to be more sensitive to environmental conditions than systemic endocrine signalling, which is essential for many non-reproductive tissues.

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Topics: Oocyte (53%), Reproductive technology (52%)


Open accessJournal ArticleDOI: 10.3390/CELLS10092292
02 Sep 2021-Cells
Abstract: Cumulus cells (CCs) originating from undifferentiated granulosa cells (GCs) differentiate in mural granulosa cells (MGCs) and CCs during antrum formation in the follicle by the distribution of location. CCs are supporting cells of the oocyte that protect the oocyte from the microenvironment, which helps oocyte growth and maturation in the follicles. Bi-directional communications between an oocyte and CCs are necessary for the oocyte for the acquisition of maturation and early embryonic developmental competence following fertilization. Follicle-stimulation hormone (FSH) and luteinizing hormone (LH) surges lead to the synthesis of an extracellular matrix in CCs, and CCs undergo expansion to assist meiotic resumption of the oocyte. The function of CCs is involved in the completion of oocyte meiotic maturation and ovulation, fertilization, and subsequent early embryo development. Therefore, understanding the function of CCs during follicular development may be helpful for predicting oocyte quality and subsequent embryonic development competence, as well as pregnancy outcomes in the field of reproductive medicine and assisted reproductive technology (ART) for infertility treatment.

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Topics: Oocyte (57%), Ovulation (55%), Human fertilization (51%)

Open accessJournal ArticleDOI: 10.1071/RD21278
Abstract: In vitro maturation (IVM) has been applied in numerous different contexts and strategies in humans and animals, but in both cases it represents a challenge still far from being overcome. Despite the large dataset produced over the last two decades on the mechanisms that govern antral follicular development and oocyte metabolism and differentiation, IVM outcomes are still unsatisfactory. This review specifically focuses on data concerning the potential consequences of using supraphysiological levels of FSH during IVM, as well as on the regulation of oocyte chromatin dynamics and its utility as a potential marker of oocyte developmental competence. Taken together, the data revisited herein indicate that a significant improvement in IVM efficacy may be provided by the integration of pre-OPU patient-specific protocols preparing the oocyte population for IVM and more physiological culture systems mimicking more precisely the follicular environment that would be experienced by the recovered oocytes until completion of metaphase II.

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Topics: Population (51%)
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71 results found


Open accessJournal ArticleDOI: 10.1016/S0092-8674(00)81279-9
Barry M. Gumbiner1Institutions (1)
09 Feb 1996-Cell
Abstract: A variety of cell adhesion mechanisms underlie the way that cells are organized in tissues. Stable cell interactions are needed to maintain the structural integrity of tissues, and dynamic changes in cell adhesion participate in the morphogenesis of developing tissues. Stable interactions actually require active adhesion mechanisms that are very similar to those involved in tissue dynamics. Adhesion mechanisms are highly regulated during tissue morphogenesis and are intimately related to the processes of cell motility and cell migration. In particular, the cadherins and the integrins have been implicated in the control of cell movement. Cadherin mediated cell compaction and cellular rearrangements may be analogous to integrin-mediated cell spreading and motility on the ECM. Regulation of cell adhesion can occur at several levels, including affinity modulation, clustering, and coordinated interactions with the actin cytoskeleton. Structural studies have begun to provide a picture of how the binding properties of adhesion receptors themselves might be regulated. However, regulation of tissue morphogenesis requires complex interactions between the adhesion receptors, the cytoskeleton, and networks of signaling pathways. Signals generated locally by the adhesion receptors themselves are involved in the regulation of cell adhesion. These regulatory pathways are also influenced by extrinsic signals arising from the classic growth factor receptors. Furthermore, signals generated locally be adhesion junctions can interact with classic signal transduction pathways to help control cell growth and differentiation. This coupling between physical adhesion and developmental signaling provides a mechanism to tightly integrate physical aspects of tissue morphogenesis with cell growth and differentiation, a coordination that is essential to achieve the intricate patterns of cells in tissues.

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Topics: Cell adhesion (70%), Morphogenesis (63%), Nectin (61%) ... read more

3,306 Citations


Journal ArticleDOI: 10.1126/SCIENCE.1092463
Jy-Young Park1, You-Qiang Su1, Miyako Ariga1, Evelyn Law1  +2 moreInstitutions (1)
30 Jan 2004-Science
Abstract: Before ovulation in mammals, a cascade of events resembling an inflammatory and/or tissue remodeling process is triggered by luteinizing hormone (LH) in the ovarian follicle. Many LH effects, however, are thought to be indirect because of the restricted expression of its receptor. Here, we demonstrate that LH stimulation induces the transient and sequential expression of the epidermal growth factor (EGF) family members amphiregulin, epiregulin, and beta-cellulin. Incubation of follicles with these growth factors recapitulates the morphological and biochemical events triggered by LH, including cumulus expansion and oocyte maturation. Thus, these EGF-related growth factors are paracrine mediators that propagate the LH signal throughout the follicle.

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Topics: Ovarian follicle (58%), Amphiregulin (54%), Epidermal growth factor (54%) ... read more

905 Citations


Open accessJournal ArticleDOI: 10.1095/BIOLREPROD.102.013029
Abstract: The objective of this study was to improve the conditions for oocyte development in vitro beginning with the primordial follicles of newborn mice. Previous studies showed that oocytes competent of meiotic maturation, fertilization, and preimplantation could develop in vitro from primordial follicles. However, the success rates were low and only one live offspring was produced (0.5% of embryos transferred). A revised protocol was compared with the original protocol using oocyte maturation and preimplantation development as end points. The percentage of oocytes maturing to metaphase II and developing to the blastocyst stage was significantly improved using the revised protocol. In addition, we compared the production of offspring from two-cell stage embryos derived from in vitro-grown and in vivo-grown oocytes. Of 1160 transferred two-cell stage embryos derived from in vitro-grown oocytes, 66 (5.7%) developed to term and 7 pups (10.6%) died at birth. The remaining 59 pups (27 females, 32 males) survived to adulthood. By comparison, of 437 transferred two-cell stage embryos derived from in vivo-grown oocytes, 76 (17.4%) developed to term and 4 (5.3%) died at birth. The remaining 72 pups (35 females, 37 males) survived to adulthood. These studies provide proof of the principle that fully competent mammalian oocytes can develop in vitro from primordial follicles and present a significant advance in oocyte culture technology.

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Topics: Oocyte (53%)

523 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1171396
Heng-Yu Fan1, Zhilin Liu1, Masayuki Shimada2, Esta Sterneck3  +3 moreInstitutions (4)
15 May 2009-Science
Abstract: A surge of luteinizing hormone (LH) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS and ERK1/2 (extracellular signal–regulated kinases 1 and 2) are activated by an LH surge in granulosa cells of preovulatory follicles, we disrupted Erk1/2 in mouse granulosa cells and provide in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrate that C/EBPβ (CCAAT/Enhancer-binding protein–β) is a critical downstream mediator of ERK1/2 activation. Thus, ERK1/2 and C/EBPβ constitute an in vivo LH-regulated signaling pathway that controls ovulation- and luteinization-related events.

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Topics: Ovarian follicle (62%), Ovulation (58%), Luteinizing hormone (57%) ... read more

471 Citations


Open accessJournal ArticleDOI: 10.1242/JCS.02562
Santos J. Franco1, Anna Huttenlocher1Institutions (1)
Abstract: The calpain family of proteases has been implicated in cellular processes such as apoptosis, proliferation and cell migration. Calpains are involved in several key aspects of migration, including: adhesion and spreading; detachment of the rear; integrin- and growth-factor-mediated signaling; and membrane protrusion. Our understanding of how calpains are activated and regulated during cell migration has increased as studies have identified roles for calcium and phospholipid binding, autolysis, phosphorylation and inhibition by calpastatin in the modulation of calpain activity. Knockout and knockdown approaches have also contributed significantly to our knowledge of calpain biology, particularly with respect to the specific functions of different calpain isoforms. The mechanisms by which calpain-mediated proteolysis of individual substrates contributes to cell motility have begun to be addressed, and these efforts have revealed roles for proteolysis of specific substrates in integrin activation, adhesion complex turnover and membrane protrusion dynamics. Understanding these mechanisms should provide avenues for novel therapeutic strategies to treat pathological processes such as tumor metastasis and chronic inflammatory disease.

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Topics: Calpain (64%), Cell migration (53%), Integrin (52%)

467 Citations