http://biostacs.com/pdf/Characterization.pdf

Characterization of microRNA profile in human cumulus granulosa cells: Identification of microRNAs that regulate Notch signaling and are associated with PCOS

Zearalenone (ZEA), one of the most prevalent estrogenic mycotoxins, is mainly produced by Fusarium fungi and has been proven to affect the reproductive capacity of animals. Exposure of farm animals to ZEA is a global public health concern because of its toxicity and wide distribution in animal feeds. In vitro and in vivo experiments indicate that ZEA possesses estrogenic activity in mice, swine, Equus asinus and cattle. The precise mechanism of the reproductive toxicity of ZEA has not been established yet. This article reviews evidence on the deleterious effects of ZEA on mammalian folliculogenesis from early to final oogenesis stages. Such effects include impaired granulosa cell (GC) development and follicle steroidogenesis, reduced oocyte nest breakdown, damaged meiotic progression, poor fetal oocyte survival, accelerated primordial follicle activation and enhanced follicle atresia. These phenomena may result in reproductive and non-reproductive problems in domestic animals. In addition, emerging data indicates that ZEA may cause mRNA expression changes in the GCs. In general, E. asinus is more sensitive than swine to ZEA exposure. Finally, results of in vivo animal studies and in vitro tests are reported and discussed.

Zearalenone: A Mycotoxin With Different Toxic Effect in Domestic and Laboratory Animals’ Granulosa Cells

The development of any organ system requires a complex interplay of cellular signals to initiate the differentiation and development of the heterogeneous cell and tissue types required to carry out the organs' functions. In this way, an extracellular stimulus is transmitted to an intracellular target through an array of interacting protein intermediaries, ultimately enabling the target cell to elicit a response. Surprisingly, only a small number of signaling pathways are implicated throughout embryogenesis and are used over and over again. Gonadogenesis is a unique process in that 2 morphologically distinct organs, the testes and ovaries, arise from a common precursor, the bipotential genital ridge. Accordingly, most of the signaling pathways observed throughout embryogenesis also have been shown to be important for mammalian sex determination and gonad development. Here, we review the mechanisms of signal transduction within these pathways and the importance of these pathways throughout mammalian gonad development, mainly concentrating on data obtained in mouse but including other species where appropriate.

/pdf/signaling-pathways-involved-in-mammalian-sex-determination-4zkgfii2jc.pdf

Signaling Pathways Involved in Mammalian Sex Determination and Gonad Development.

DEHP exposure impairs mouse oocyte cyst breakdown and primordial follicle assembly through estrogen receptor-dependent and independent mechanisms

Each follicle represents the basic functional unit of the ovary From its very initial stage of development, the follicle consists of an oocyte surrounded by somatic cells The oocyte grows and matures to become fertilizable and the somatic cells proliferate and differentiate into the major suppliers of steroid sex hormones as well as generators of other local regulators The process by which a follicle forms, proceeds through several growing stages, develops to eventually release the mature oocyte, and turns into a corpus luteum (CL) is known as "folliculogenesis" The task of this review is to define the different stages of folliculogenesis culminating at ovulation and CL formation, and to summarize the most recent information regarding the newly identified factors that regulate the specific stages of this highly intricated process This information comprises of either novel regulators involved in ovarian biology, such as Ube2i, Phoenixin/GPR73, C1QTNF, and α-SNAP, or recently identified members of signaling pathways previously reported in this context, namely PKB/Akt, HIPPO, and Notch

https://www.mdpi.com/1422-0067/21/12/4565/pdf

Newly Identified Regulators of Ovarian Folliculogenesis and Ovulation.

Ovarian follicles form through a process in which somatic pregranulosa cells encapsulate individual germ cells from germ cell syncytia. Complementary expression of the Notch ligand, Jagged1, in germ cells and the Notch receptor, Notch2, in pregranulosa cells suggests a role for Notch signaling in mediating cellular interactions during follicle assembly. Using a Notch reporter mouse, we demonstrate that Notch signaling is active within somatic cells of the embryonic ovary, and these cells undergo dramatic reorganization during follicle histogenesis. This coincides with a significant increase in the expression of the ligands, Jagged1 and Jagged2; the receptor, Notch2; and the target genes, Hes1 and Hey2. Histological examination of ovaries from mice with conditional deletion of Jagged1 within germ cells (J1 knockout [J1KO]) or Notch2 within granulosa cells (N2 knockout [N2KO]) reveals changes in follicle dynamics, including perturbations in the primordial follicle pool and antral follicle development. J1KO and N2KO ovaries also contain multi-oocytic follicles, which represent a failure to resolve germ cell syncytia, and follicles with enlarged oocytes but lacking somatic cell growth, signifying a potential role of Notch signaling in follicle activation and the coordination of follicle development. We also observed decreased cell proliferation and increased apoptosis in the somatic cells of both conditional knockout lines. As a consequence of these defects, J1KO female mice are subfertile; however, N2KO female mice remain fertile. This study demonstrates important functions for Jagged1 and Notch2 in the resolution of germ cell syncytia and the coordination of somatic and germ cell growth within follicles of the mouse ovary.

/pdf/notch-signaling-regulates-ovarian-follicle-formation-and-52w4vghj0m.pdf

Notch Signaling Regulates Ovarian Follicle Formation and Coordinates Follicular Growth

The Notch pathway is a highly conserved juxtacrine signaling mechanism that is important for many cellular processes during development, including differentiation and proliferation. Although Notch is important during ovarian follicle formation and early development, its functions during the gonadotropin-dependent stages of follicle development are largely unexplored. We observed positive regulation of Notch activity and expression of Notch ligands and receptors following activation of the luteinizing hormone-receptor in prepubertal mouse ovary. JAG1, the most abundantly expressed Notch ligand in mouse ovary, revealed a striking shift in localization from oocytes to somatic cells following hormone stimulation. Using primary cultures of granulosa cells, we investigated the functions of Jag1 using small interfering RNA knockdown. The loss of JAG1 led to suppression of granulosa cell differentiation as marked by reduced expression of enzymes and factors involved in steroid biosynthesis, and in steroid secretion. Jag1 knockdown also resulted in enhanced cell proliferation. These phenotypes were replicated, although less robustly, following knockdown of the obligate canonical Notch transcription factor RBPJ. Intracellular signaling analysis revealed increased activation of the mitogenic phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways following Notch knockdown, with a mitogen-activated protein kinase kinase inhibitor blocking the enhanced proliferation observed in Jag1 knockdown granulosa cells. Activation of YB-1, a known regulator of granulosa cell differentiation genes, was suppressed by Jag1 knockdown. Overall, this study reveals a role of Notch signaling in promoting the differentiation of preovulatory granulosa cells, adding to the diverse functions of Notch in the mammalian ovary.

Notch Signaling Regulates Differentiation and Steroidogenesis in Female Mouse Ovarian Granulosa Cells.

The Notch pathway plays diverse and complex roles in cell signaling during development. In the mammalian ovary, Notch is important for the initial formation and growth of follicles, and for regulating the proliferation and differentiation of follicular granulosa cells during the periovulatory period. This study seeks to determine the contribution of female germ cells toward the initial activation and subsequent maintenance of Notch signaling within somatic granulosa cells of the ovary. To address this issue, transgenic Notch reporter (TNR) mice were crossed with Sohlh1-mCherry (S1CF) transgenic mice to visualize Notch-active cells (EGFP) and germ cells (mCherry) simultaneously in the neonatal ovary. To test the involvement of oocytes in activation of Notch signaling in ovarian somatic cells, we ablated germ cells using busulfan, a chemotherapeutic alkylating agent, or investigated KitWv/Wv (viable dominant white-spotting) mice that lack most germ cells. The data reveal that Notch pathway activation in granulosa cells is significantly suppressed when germ cells are reduced. We further demonstrate that disruption of the gene for the Notch ligand Jag1 in oocytes similarly impacts Notch activation and that recombinant JAG1 enhances Notch target gene expression in granulosa cells. These data are consistent with the hypothesis that germ cells provide a ligand, such as Jag1, that is necessary for activation of Notch signaling in the developing ovary.

/pdf/activation-of-notch-signaling-by-oocytes-and-jag1-in-mouse-1ni1879iso.pdf

Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells

The follicle is the functional unit of the mammalian ovary and serves as a tightly controlled microenvironment where granulosa cells nurture the growth and maturation of the oocyte. Early events in follicular development are autonomous of the hypothalamic-pituitary-gonadal axis and are instead controlled by local factors that are used in bidirectional communication between oocytes and somatic cells. While gonadotropins will eventually become the principle regulators of follicular growth, maturation, and ovulation, it is becoming appreciated that their actions are achieved through interactions with local intraovarian signals. The use of genetic tools developed in murine models has led to the discovery of vast networks of oocyte-, granulosa cell-, thecal cell-, and stromal cell-derived factors that govern gonadotropin-independent follicular development. Many of these discoveries from rodent models have proved broadly applicable to other mammalian systems. We summarize current knowledge of how local juxtacrine and paracrine signaling pathways control follicular development and interact with gonadotropin signaling to ensure female fertility and reproductive health.

Regulation of Follicle Formation and Development by Ovarian Signaling Pathways

DNA methylation erasure is required for mammalian primordial germ cell reprogramming. TET enzymes iteratively oxidize 5-methylcytosine to generate 5-hyroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxycytosine to facilitate active genome demethylation. Whether these bases are required to promote replication-coupled dilution or activate base excision repair during germline reprogramming remains unresolved due to the lack of genetic models that decouple TET activities. Here, we generated two mouse lines expressing catalytically inactive TET1 (Tet1-HxD) and TET1 that stalls oxidation at 5hmC (Tet1-V). Tet1-/-, Tet1V/V, and Tet1HxD/HxD sperm methylomes show that TET1V and TET1HxD rescue most Tet1-/- hypermethylated regions, demonstrating the importance of TET1’s extra-catalytic functions. Imprinted regions, in contrast, require iterative oxidation. We further reveal a broader class of hypermethylated regions in sperm of Tet1 mutant mice that are excluded from de novo methylation during male germline development and depend on TET oxidation for reprogramming. Our study underscores the link between TET1-mediated demethylation during reprogramming and sperm methylome patterning.

/pdf/tet1-catalytic-activity-is-required-for-reprogramming-of-1qp57too.pdf

Rexxi D. Prasasya

Papers

Notch Signaling Regulates Ovarian Follicle Formation and Coordinates Follicular Growth

Notch Signaling Regulates Differentiation and Steroidogenesis in Female Mouse Ovarian Granulosa Cells.

Activation of Notch Signaling by Oocytes and Jag1 in Mouse Ovarian Granulosa Cells

Regulation of Follicle Formation and Development by Ovarian Signaling Pathways

TET1 Catalytic Activity is Required for Reprogramming of Imprinting Control Regions and Patterning of Sperm-Specific Hypomethylated Regions