Effects of Neuroendocrine CB1 Activity on Adult Leydig Cells

Cobellis, Gilda; Meccariello, Rosaria; Chianese, Rosanna; Chioccarelli, Teresa; Fasano, Silvia; Pierantoni, Riccardo

doi:10.3389/fendo.2016.00047

Cited by 21 publications

(20 citation statements)

References 51 publications

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“…Based on the hypothesis that linear transcripts and their circular counterparts could have potential biological and molecular relationships [55][56][57], we chose genes having an important function in SPZ biology, whose linear transcripts are abundant in SPZ or testis, as hosts for candidate circRNAs. More specifically, we focused on components of the endocannabinoid system (CNR1, CNR2, FAAH, NAPEPLD) [58][59][60][61][62], modulators of protein folding (DNAJB1, DNAJB3 [2,63], HSP90AA1 [64]; HSPA1B, HSPD1 [65]), intragonadic regulators (AR, ESR1, ESR2, GNRH1, GNRHR, GPER1, KISS1, KISS1R) [2,3,66,67]; (LEP, LEPR) [68]; MTHFR [69], PIWIL1 [70]; RARA [71]; RXFP1 [72]; SIRT1 [73]] and epididymal markers (ADAM7 [74], GLIPR1L1 [75], NPC2 [76], SPAM1 [77]). Querying circBase database (http://www.circbase.org/), we found that only six of the previously selected linear RNAs had HS and MM homologous circular isoform counterparts.…”

Section: Identification Of Candidate Spz-related Circrnas In Homo Sapmentioning

confidence: 99%

CircNAPEPLD is expressed in human and murine spermatozoa and physically interacts with oocyte miRNAs

et al. 2019

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Circular RNAs (circRNAs) have a critical role in the control of gene expression. Their function in spermatozoa (SPZ) is unknown to date. Twenty-eight genes, involved in SPZ/testicular and epididymal physiology, were given in circBase database to find which of them may generate circular transcripts. We focused on circNAPEPLDiso1, one of the circular RNA isoforms of NAPEPLD transcript, because expressed in human and murine SPZ. In order to functionally characterize circNAPEPLDiso1 as potential microRNA (miRNA) sponge, we performed circNAPEPLDiso1-miR-CATCH and then profiled the expression of 754 miRNAs, by using TaqMan® Low Density Arrays. Among them, miRNAs 146a-5p, 203a-3p, 302c-3p, 766-3p and 1260a (some of them previously shown to be expressed in the oocyte), resulted enriched in circNAPEPLDiso1-miR-CATCHed cell lysate: the network of interactions generated from their validated targets was centred on a core of genes involved in the control of cell cycle. Moreover, computational analysis of circNAPEPLDiso1 sequence also showed its potential translation in a short form of NAPEPLD protein. Interestingly, the expression analysis in murine-unfertilized oocytes revealed low and high levels of circNAPEPLDiso1 and circNAPEPLDiso2, respectively. After fertilization, circNAPEPLDiso1 expression significantly increased, instead circNAPEPLDiso2 expression appeared constant. Based on these data, we suggest that SPZ-derived circNAPEPLDiso1 physically interacts with miRNAs primarily involved in the control of cell cycle; we hypothesize that it may represent a paternal cytoplasmic contribution to the zygote and function as a miRNA decoy inside the fertilized oocytes to regulate the first stages of embryo development. This role is proposed here for the first time.

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Section: Identification Of Candidate Spz-related Circrnas In Homo Sapmentioning

confidence: 99%

CircNAPEPLD is expressed in human and murine spermatozoa and physically interacts with oocyte miRNAs

et al. 2019

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“…The components of this system have been identified in mammalian and non-mammalian testes, in somatic and germ cells, from SPG to SPZ ( 21 , 43 , 44 , 46 , 49 – 56 ). CB1 has been localized in differentiating/mature adult Leydig cells, in SPT and SPZ and it seems to be positively related to (i) steroidogenesis ( 20 – 22 , 56 ) and differentiation ( 49 ) of Leydig cell, (ii) chromatin remodeling ( 7 , 57 ) of SPT, and (iii) maturation and quality of SPZ ( 44 , 46 , 47 , 51 , 52 , 54 , 55 , 58 ). Interestingly, in rat testis, a weak and stage-specific expression of CB1 has been observed in Sertoli cells ( 22 , 49 ) when SPT appear in seminiferous tubules.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Endocannabinoid System in Rat Testis During the First Spermatogenetic Wave

et al. 2018

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Endocannabinoids are lipid mediators, enzymatically synthesized and hydrolyzed, that bind cannabinoid receptors. Together with their receptors and metabolic enzymes, they form the “endocannabinoid system” (ECS). Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the main endocannabinoids studied in testis. In this study, using the first wave of spermatogenesis as an in vivo model to verify the progressive appearance of germ cells in seminiferous tubules [i.e., spermatogonia, spermatocytes, and spermatids], we analyzed the expression of the main enzymes and receptors of ECS in rat testis. In particular, the expression profile of the main enzymes metabolizing AEA and 2-AG as well as the expression of cannabinoid receptors, such as CB1 and CB2, and specific markers of mitotic, meiotic, and post-meiotic germ cell appearance or activities have been analyzed by RT-PCR and appropriately correlated. Our aim was to envisage a relationship between expression of ECS components and temporal profile of germ cell appearance or activity as well as among ECS components. Results show that expression of ECS components is related to germ cell progression. In particular, CB2 and 2-AG appear to be related to mitotic/meiotic stages, while CB1 and AEA appear to be related to spermatogonia stem cells activity and spermatids appearance, respectively. Our data also suggest that a functional interaction among ECS components occurs in the testis. Indeed, in vitro-incubated testis show that AEA-CB2 activity affects negatively monoacylglycerol-lipase levels via upregulation of CB1 suggesting a CB1/CB2-mediated relationship between AEA and 2-AG. Finally, we provide the first evidence that CB1 is present in fetal gonocytes, during mitotic arrest.

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“…A significant reduction of serum LH and testosterone, as well as lower in vitro basal secretion of testosterone, have been noticed in CB 1 –/– mice, with AEA suppressing LH and testosterone secretion in wild-type mice but not in knockout animals [ 45 ]. Moreover, the presence of CB 1 in Leydig cells and its leading role in testosterone secretion confirm the importance of eCBs in modulating Leydig cells functions and testis endocrinology [ 41 , 46 ]. Particularly, CB 1 expression in differentiating rat adult Leydig cells is also negatively correlated with cell proliferation, and the presence of few adult Leydig cells in CB 1 –/– mice points to the ECS as a potential modulator of proliferative activity involved in adult Leydig cells differentiation [ 47 ] and may also explain the lower in vitro basal testosterone secretion in CB 1 –/– mice [ 45 ].…”

Section: Introductionmentioning

confidence: 86%

Artificial Neural Network to Predict Varicocele Impact on Male Fertility through Testicular Endocannabinoid Gene Expression Profiles

Perruzza

Bernabò

Rapino

et al. 2018

BioMed Research International

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The relationship between varicocele and fertility has always been a matter of debate because of the absence of predictive clinical indicators or molecular markers able to define the severity of this disease. Even though accumulated evidence demonstrated that the endocannabinoid system (ECS) plays a central role in male reproductive biology, particularly in the testicular compartment, to date no data point to a role for ECS in the etiopathogenesis of varicocele. Therefore, the present research has been designed to investigate the relationship between testicular ECS gene expression and fertility, using a validated animal model of experimental varicocele (VAR), taking advantage of traditional statistical approaches and artificial neural network (ANN). Experimental induction of VAR led to a clear reduction of spermatogenesis in left testes ranging from a mild (Johnsen score 7: 21%) to a severe (Johnsen score 4: 58%) damage of the germinal epithelium. However, the mean number of new-borns recorded after two sequential matings was quite variable and independent of the Johnsen score. While the gene expression of biosynthetic and degrading enzymes of AEA (NAPE-PLD and FAAH, respectively) and of 2-AG (DAGLα and MAGL, respectively), as well as their binding cannabinoid receptors (CB1 and CB2), did not change between testes and among groups, a significant downregulation of vanilloid (TRPV1) expression was recorded in left testes of VAR rats and positively correlated with animal fertility. Interestingly, an ANN trained by inserting the left and right testicular ECS gene expression profiles (inputs) was able to predict varicocele impact on male fertility in terms of mean number of new-borns delivered (outputs), with a very high accuracy (average prediction error of 1%). The present study provides unprecedented information on testicular ECS gene expression patterns during varicocele, by developing a freely available predictive ANN model that may open new perspectives in the diagnosis of varicocele-associated infertility.

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Effects of Neuroendocrine CB1 Activity on Adult Leydig Cells

Cited by 21 publications

References 51 publications

CircNAPEPLD is expressed in human and murine spermatozoa and physically interacts with oocyte miRNAs

CircNAPEPLD is expressed in human and murine spermatozoa and physically interacts with oocyte miRNAs

Analysis of Endocannabinoid System in Rat Testis During the First Spermatogenetic Wave

Artificial Neural Network to Predict Varicocele Impact on Male Fertility through Testicular Endocannabinoid Gene Expression Profiles

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