Orphan nuclear receptors in angiogenesis and follicular development

Orphan nuclear receptors (ONRs) are a subset of the nuclear receptor family that lack known endogenous ligands. Among 48 nuclear receptors identified in humans, 25 are classified as ONRs. They function as transcription factors and control expression of a wide range of genes to regulate metabolism, fertility, immunity, angiogenesis, and many other functions. Angiogenic factors are essential during ovarian follicle development, including follicle growth and ovulation,. Correct development of blood vessels contributes to preantral and antral follicular development, selection of the dominant follicle or follicles, follicular atresia, and ovulation. Although progress has been made in understanding the molecular mechanisms that regulate follicular angiogenesis, the role of ONRs as regulators is not clear. Based on their functions in other tissues, the ONRs NR1D1 (REV-ERBß), NR2C2 (TR4), NR2F2 (COUP-TF-II) and NR3B1, 2, and 3 (ERRα, ERRß and ERRγ) may modulate angiogenesis during antral follicle development. We hypothesize that this is achieved by effects on the expression and function of VEGFA, ANGPT1, THBS1, and soluble VEGFR1. Further, angiogenesis during ovulation is expected to be influenced by ONRs. NR5A2 (LRH-1), which is required for ovulation, regulates angiogenic genes in the ovary, including VEGFA and the upstream regulator of angiogenesis, PGE2. These angiogenic molecules may also be regulated by NR5A1 (SF-1). Evidence from outside the reproductive tract suggests that NR2F2 and NR4A1(NUR77) promote VEGFC and PGF respectively and NR4As (ΝUR77, NOR1) seem to be necessary for the angiogenic effects of VEGFA and PGE2. Together, the data suggest that ONRs are important regulators of follicular angiogenesis.

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Lnc-GULP1-2:1 affects granulosa cell proliferation by regulating COL3A1 expression and localization

10.21203/rs.3.rs-72763/v3 ◽

2021 ◽

Author(s):

Guidong Yao ◽

Yue Kong ◽

Guang Yang ◽

Deqi Kong ◽

Yijiang Xu ◽

...

Keyword(s):

Cell Proliferation ◽

Granulosa Cells ◽

Molecular Mechanisms ◽

Polycystic Ovary ◽

Ovarian Follicle ◽

Follicular Development ◽

Protein Coding ◽

Ovarian Follicle Development ◽

Multiple Cell ◽

Ovarian Follicular Development

Abstract Backgrounds: Long non-coding RNA is a novel group of non-protein coding transcripts over 200nt in length. Recent studies have found that they are widely involved in many pathological and physiological processes. In our previous study, we found that lnc-GULP1-2:1 was significantly down-regulated in the ovarian cortical tissue of patients with primary ovarian insufficiency and predicted that lnc-GULP1-2:1 has a regulatory effect on COL3A1. Results: In this study, we found that lnc-GULP1-2:1 was mainly localized in the cytoplasm of luteinized granulosa cells. The expression of lnc-GULP1-2:1 was lower in patients with diminished ovarian reserve but substantially elevated in patients with polycystic ovary syndrome. Overexpression of lnc-GULP1-2:1 in KGN cells significantly inhibited cell proliferation, likely through cell cycle related genes CCND2 and p16. Moreover, lnc-GULP1-2:1 expression was positively correlated with the level of COL3A in luteinized granulosa cells from patients with different ovarian functions as well as in multiple cell lines. Overexpression of lnc-GULP1-2:1 in KGN cells promoted the expression of COL3A1 and its translocation into the nucleus. Consistently, silencing COL3A1 in KGN cells also significantly inhibited cell proliferation. Conclusions: Lnc-GULP1-2:1 affects the proliferation of granulosa cells by regulating the expression and localization of COL3A1 protein, and may participate in the regulation of ovarian follicle development. This study will provide new insight into molecular mechanisms underlying ovarian follicular development, which will help generate novel diagnostic and therapeutic strategies for diseases related to ovarian follicular development disorders.

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224 OVARIAN FOLLICLE DEVELOPMENT DURING SEASONAL TRANSITION IN WAPITI

Reproduction Fertility and Development ◽

10.1071/rdv18n2ab224 ◽

2006 ◽

Vol 18 (2) ◽

pp. 220

Author(s):

R. McCorkell ◽

M. Woodbury ◽

G. Adams

Keyword(s):

Breeding Season ◽

Ovarian Follicle ◽

Follicular Development ◽

Maximum Diameter ◽

Follicle Development ◽

Estrous Cycles ◽

Ovarian Follicle Development ◽

Array Transducer ◽

October 17 ◽

Ovulatory Follicles

Wapiti are seasonally polyestrous. The transition into and out of the breeding season is marked by resumption of ovulation in autumn and cessation of ovulation in winter. Onset of ovulatory cyclicity is distinct and associated with aggressive breeding behavior of stags in rut. Cessation of ovulation at the end of the breeding season is not distinguished by behavioral patterns. The objective of the present study was to characterize follicular and luteal dynamics in wapiti during the transitional periods into and out of the breeding seasons. Transition from anestrus to estrus was monitored in 15 hinds, aged 2 to 14 years, over two successive seasons (11 in year 1, with 5 hinds from year 1 used again in year 2 along with 4 new hinds; n = 20 observations). Transition from estrus to anestrus was monitored in 11 hinds over 1 season (n = 11 observations). Hinds were maintained on a farm near Saskatoon, Saskatchewan (52°07′N, 106°38′W). The ovaries were examined daily during September through October by transrectral ultrasonography using a B-mode ultrasound machine and a 7.5 MHz linear array transducer for transition to estrus, and December through April for transition to anestrus. The first ovulation was recorded on September 15 and all hinds had ovulated for the first time by October 7. In 17 of 20 observations, the duration of the first interovulatory interval (IOI) was 9.3 ± 0.4 days (mean ± SEM). With one exception, these IOIs were characterized by one wave of follicular development. The remaining three IOIs ranged from 16 to 23 days and consisted of two or three waves of follicle development. The second ovulation occurred by October 15 in hinds with a short IOI and by October 17 in all remaining hinds. The mean dates of first and last ovulation were September 25 and February 7, respectively, an interval of 135 days. The median date of the last ovulation was February 15 and the range was from December 3 to March 22. Duration of the last IOI of the season (21.2 ± 0.6 days) was similar to the notional 21-day cycle for wapiti, but longer (P < 0.05) than the duration of the first IOI (10.9 ± 1.0 days). Maximum diameters of the first 2 ovulatory follicles were similar (11.3 ± 0.4 vs. 11.3 ± 0.2 mm), but were larger (P < 0.05) than the last 2 ovulatory follicles of the breeding season (10.3 ± 0.3 vs. 10.1 ± 0.4 mm). Maximum diameter of the corpus luteum (CL) tended (P = 0.06) to be smaller for the short IOI than for longer IOI of the first and last cycles. Diameter of the last CL of the season was not different from that of the previous CL (12.8 ± 0.6 vs. 12.5 ± 0.6 mm); however, it was detected for a longer period (22.3 ± 1.2 vs. 19.3 ± 0.7 days; P < 0.05). Estrous cycles during transition into the breeding season have been described as being irregular and those out of the breeding season as increasingly long. In the present study, the transition periods were characterized by regular events. Transition to regular estrous cycles was preceded by one short (9 days) IOI. The last IOI of the breeding season was the same as that reported during the rut. Transition to anestrus occurred most commonly in February and was marked by a failure of the dominant follicle to ovulate after luteal regression.

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Lnc-GULP1–2:1 affects granulosa cell proliferation by regulating COL3A1 expression and localization

Journal of Ovarian Research ◽

10.1186/s13048-021-00769-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Guidong Yao ◽

Yue Kong ◽

Guang Yang ◽

Deqi Kong ◽

Yijiang Xu ◽

...

Keyword(s):

Cell Proliferation ◽

Granulosa Cells ◽

Molecular Mechanisms ◽

Polycystic Ovary ◽

Ovarian Follicle ◽

Follicular Development ◽

Protein Coding ◽

Ovarian Follicle Development ◽

Multiple Cell ◽

Ovarian Follicular Development

Abstract Backgrounds Long non-coding RNA is a novel group of non-protein coding transcripts over 200 nt in length. Recent studies have found that they are widely involved in many pathological and physiological processes. In our previous study, we found that lnc-GULP1–2:1 was significantly down-regulated in the ovarian cortical tissue of patients with primary ovarian insufficiency and predicted that lnc-GULP1–2:1 has a regulatory effect on COL3A1. Results In this study, we found that lnc-GULP1–2:1 was mainly localized in the cytoplasm of luteinized granulosa cells. The expression of lnc-GULP1–2:1 was lower in patients with diminished ovarian reserve but substantially elevated in patients with polycystic ovary syndrome. Overexpression of lnc-GULP1–2:1 in KGN cells significantly inhibited cell proliferation, likely through cell cycle related genes CCND2 and p16. Moreover, lnc-GULP1–2:1 expression was positively correlated with the level of COL3A in luteinized granulosa cells from patients with different ovarian functions as well as in multiple cell lines. Overexpression of lnc-GULP1–2:1 in KGN cells promoted the expression of COL3A1 and its translocation into the nucleus. Consistently, silencing COL3A1 in KGN cells also significantly inhibited cell proliferation. Conclusions Lnc-GULP1–2:1 affects the proliferation of granulosa cells by regulating the expression and localization of COL3A1 protein, and may participate in the regulation of ovarian follicle development. This study will provide new insight into molecular mechanisms underlying ovarian follicular development, which will help generate novel diagnostic and therapeutic strategies for diseases related to ovarian follicular development disorders.

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Differential expression of mRNAs encoding the putative inhibin co-receptor (betaglycan) and activin type-I and type-II receptors in preovulatory and prehierarchical follicles of the laying hen ovary

Journal of Endocrinology ◽

10.1677/joe.1.06525 ◽

2006 ◽

Vol 188 (2) ◽

pp. 241-249 ◽

Cited By ~ 8

Author(s):

T M Lovell ◽

P G Knight ◽

R T Gladwell

Keyword(s):

Mrna Expression ◽

Transforming Growth Factor ◽

Ovarian Follicle ◽

Follicular Development ◽

Transforming Growth Factor Β ◽

Receptor Expression ◽

Type I ◽

Follicle Development ◽

Ovarian Follicle Development ◽

Real Time Quantitative Pcr

Ovarian follicle development is primarily regulated by an interplay between the pituitary gonadotrophins, LH and FSH, and ovary-derived steroids. Increasing evidence implicates regulatory roles of transforming growth factor-β (TGFβ) superfamily members, including inhibins and activins. The aim of this study was to identify the expression of mRNAs encoding key receptors of the inhibin/activin system in ovarian follicles ranging from 4 mm in diameter to the dominant F1 follicle (~40 mm). Ovaries were collected (n=16) from mid-sequence hens maintained on a long-day photoschedule (16 h of light:8 h of darkness). All follicles removed were dissected into individual granulosa and thecal layers. RNA was extracted and cDNA synthesized. Real-time quantitative PCR was used to quantify the expression of mRNA encoding betaglycan, activin receptor (ActR) subtypes (type-I, -IIA and -IIB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH); receptor expression data were normalized to GAPDH expression. Detectable levels of ActRI, -IIA and -IIB and the inhibin co-receptor (betaglycan) expression were found in all granulosa and thecal layers analysed. Granulosa ActRI mRNA peaked (P < 0.05) in 8–9.9 mm follicles, whereas ActRIIA rose significantly from 6–7.9 mm to 8–9.9 mm, before falling to F3/2; levels then rose sharply (3-fold) to F1 levels. Granulosa betaglycan mRNA expression rose 3-fold from 4–5.9 mm to 8–9.9 mm, before falling 4-fold to F3/2; levels then rose sharply (4-fold) to F1 levels. ActRIIB levels did not vary significantly during follicular development. Thecal ActRI mRNA expression was similar from 4–7.9 mm then decreased significantly to a nadir at the F4 position, before increasing 2-fold to the F1 (P < 0.05). Although thecal ActRIIB and -IIA expression did not vary significantly from 4 mm to F3, ActRIIB expression increased significantly (2-fold) from F3 to F1 and ActRIIA increased 2-fold from F2 to F1 (P < 0.05). Thecal betaglycan fell to a nadir at F6 after follicle selection; levels then increased significantly to F2, before falling ~50% in the F1. In all follicles studied expression of betaglycan and ActRI (granulosa: r=0.65, P < 0.001, n=144/group; theca: r=0.49, P < 0.001, n=144/group) was well correlated. No significant correlations were identified between betaglycan and ActRIIA or -IIB. Considering all follicles analysed, granulosa mRNA expression of betaglycan, ActRI, ActRIIA and ActRIIB were all significantly lower than in corresponding thecal tissue (betaglycan, 11.4-fold; ActRIIB, 5.1-fold; ActRI, 3.8-fold; ActRIIA, 2.8-fold). The co-localization of type-I and -II activin receptors and betaglycan on granulosa and thecal cells are consistent with a local auto/paracrine role of inhibins and activins in modulating ovarian follicle development, selection and progression in the domestic fowl.

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The Signaling Pathways Involved in Ovarian Follicle Development

Frontiers in Physiology ◽

10.3389/fphys.2021.730196 ◽

2021 ◽

Vol 12 ◽

Author(s):

Liyuan Li ◽

Xiaojin Shi ◽

Yun Shi ◽

Zhao Wang

Keyword(s):

Signaling Pathways ◽

Signaling Pathway ◽

Ovarian Follicle ◽

Follicular Development ◽

Follicle Cells ◽

Follicle Development ◽

Akt Signaling Pathway ◽

Ovarian Follicle Development ◽

High Possibility

The follicle is the functional unit of the ovary, which is composed of three types of cells: oocytes, granulosa cells, and theca cells. Ovarian follicle development and the subsequent ovulation process are coordinated by highly complex interplay between endocrine, paracrine, and autocrine signals, which coordinate steroidogenesis and gametogenesis. Follicle development is regulated mainly by three organs, the hypothalamus, anterior pituitary, and gonad, which make up the hypothalamic-pituitary-gonadal axis. Steroid hormones and their receptors play pivotal roles in follicle development and participate in a series of classical signaling pathways. In this review, we summarize and compare the role of classical signaling pathways, such as the WNT, insulin, Notch, and Hedgehog pathways, in ovarian follicle development and the underlying regulatory mechanism. We have also found that these four signaling pathways all interact with FOXO3, a transcription factor that is widely known to be under control of the PI3K/AKT signaling pathway and has been implicated as a major signaling pathway in the regulation of dormancy and initial follicular activation in the ovary. Although some of these interactions with FOXO3 have not been verified in ovarian follicle cells, there is a high possibility that FOXO3 plays a core role in follicular development and is regulated by classical signaling pathways. In this review, we present these signaling pathways from a comprehensive perspective to obtain a better understanding of the follicular development process.

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Notch Signaling Is Involved in Ovarian Follicle Development by Regulating Granulosa Cell Proliferation

Endocrinology ◽

10.1210/en.2010-1182 ◽

2011 ◽

Vol 152 (6) ◽

pp. 2437-2447 ◽

Cited By ~ 60

Author(s):

Chun-Ping Zhang ◽

Jun-Ling Yang ◽

Jun Zhang ◽

Lei Li ◽

Lin Huang ◽

...

Keyword(s):

Cell Proliferation ◽

Notch Signaling ◽

Granulosa Cell ◽

Granulosa Cells ◽

Ovarian Follicle ◽

Butyl Ester ◽

Follicular Development ◽

Follicle Development ◽

Ovarian Follicle Development

Notch signaling is an evolutionarily conserved pathway, which regulates cell proliferation, differentiation, and apoptosis. It has been reported that the members of Notch signaling are expressed in mammalian ovaries, but the exact functions of this pathway in follicle development is still unclear. In this study, primary follicles were cultured in vitro and treated with Notch signaling inhibitors, L-658,458 and N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). We found that the cultured follicles completely stopped developing after L-658,458 and DAPT treatment, most of the granulosa cells were detached, and the oocytes were also degenerated with condensed cytoplasma. Further studies demonstrated that the proliferation of granulosa cells was dependent on the Notch signaling. L-658,458 and DAPT treatment inhibited proliferation of in vitro cultured primary granulosa cells and decreased the expression of c-Myc. Lentivirus mediated overexpression of Notch intracellular domain 2, and c-Myc could promote the proliferation of granulosa cells and rescue the growth inhibition induced by L-658,458 and DAPT. In conclusion, Notch signaling is involved in follicular development by regulating granulosa cell proliferation.

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Transcriptome comparative analysis of ovarian follicles reveals the key genes and signaling pathways implicated in hen egg production

BMC Genomics ◽

10.1186/s12864-021-08213-w ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Xue Sun ◽

Xiaoxia Chen ◽

Jinghua Zhao ◽

Chang Ma ◽

Chunchi Yan ◽

...

Keyword(s):

Signaling Pathways ◽

Cell Apoptosis ◽

Egg Production ◽

Caspase 3 ◽

Developmental Stages ◽

Ovarian Follicle ◽

Follicular Development ◽

Egg Laying ◽

Follicle Development ◽

Ovarian Follicle Development

Abstract Background Ovarian follicle development plays an important role in determination of poultry egg production. The follicles at the various developmental stages possess their own distinct molecular genetic characteristics and have different biological roles in chicken ovary development and function. In the each stage, several genes of follicle-specific expression and biological pathways are involved in the vary-sized follicular development and physiological events. Identification of the pivotal genes and signaling pathways that control the follicular development is helpful for understanding their exact regulatory functions and molecular mechanisms underlying egg-laying traits of laying hens. Results The comparative mRNA transcriptomic analysis of ovarian follicles at three key developmental stages including slow growing white follicles (GWF), small yellow follicles (SYF) of recruitment into the hierarchy, and differentiated large yellow follicles (LYF), was accomplished in the layers with lower and higher egg production. Totally, 137, 447, and 229 of up-regulated differentially expressed genes (DEGs), and 99, 97, and 157 of down-regulated DEGs in the GWF, SYF and LYF follicles, including VIPR1, VIPR2, ADRB2, and HSD17B1 were identified, respectively. Moreover, NDUFAB1 and GABRA1 genes, two most promising candidates potentially associated with egg-laying performance were screened out from the 13 co-expressed DEGs in the GWF, SYF and LYF samples. We further investigated the biological effects of NDUFAB1 and GABRA1 on ovarian follicular development and found that NDUFAB1 promotes follicle development by stimulating granulosa cell (GC) proliferation and decreasing cell apoptosis, increases the expression of CCND1 and BCL-2 but attenuates the expression of caspase-3, and facilitates steroidogenesis by enhancing the expression of STAR and CYP11A1. In contrast, GABRA1 inhibits GC proliferation and stimulates cell apoptosis, decreases the expression of CCND1, BCL-2, STAR, and CYP11A1 but elevates the expression of caspase-3. Furthermore, the three crucial signaling pathways such as PPAR signaling pathway, cAMP signaling pathway and neuroactive ligand-receptor interaction were significantly enriched, which may play essential roles in ovarian follicle growth, differentiation, follicle selection, and maturation. Conclusions The current study provided new molecular data for insight into the regulatory mechanism underlying ovarian follicle development associated with egg production in chicken.

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