Undifferentiated spermatogonia regulate<i>Cyp26b1</i>expression through NOTCH signaling and drive germ cell differentiation

Parekh, Parag; Garcia, Thomas; Waheeb, Reham; Jain, Vivek; Gandhi, Poojabahen; Meistrich, Marvin L.; Shetty, Gunapala; Hofmann, Marie‐Claude

doi:10.1096/fj.201802361r

Cited by 26 publications

(25 citation statements)

References 69 publications

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“…To date the significance of Notch1/HES1/HEY1 pathway in the testis was precisely determined only in Sertoli cells. It was established that HES1 and HEY1 inhibit the production of glial cell line-derived neurotrophic factor (GDNF) and expression of retinoid acid metabolizing enzyme CYP26B1 by Sertoli cells [42,45]. The results by Murta et al [13] suggested also a regulatory role of Notch signaling in spermatid elongation and maintenance of the elongated spermatid anchoring system.…”

Section: Discussionmentioning

confidence: 99%

Disruption of androgen signaling during puberty affects Notch pathway in rat seminiferous epithelium

Kamińska

Marek

Pardyak

et al. 2020

Reprod Biol Endocrinol

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Background: Onset of spermatogenesis at puberty is critically dependent on the activity of hypothalamic-pituitarygonadal axis and testosterone production by Leydig cells. The aim of this study was to examine whether activation of Notch receptors and expression of Notch ligands and effector genes in rat seminiferous epithelium are controlled by androgen signaling during puberty. Methods: Peripubertal (5-week-old) Wistar rats received injections of flutamide (50 mg/kg bw) daily for 7 days to reduce androgen receptor (AR) signaling or a single injection of ethanedimethane sulphonate (EDS; 75 mg/kg bw) to reduce testosterone production. Gene and protein expressions were analyzed by real-time RT-PCR and western blotting, respectively, protein distribution by immunohistochemistry, and steroid hormone concentrations by enzymelinked immunosorbent assay. Statistical analyses were performed using one-way ANOVA followed by Tukey's post hoc test or by Kruskal-Wallis test, followed by Dunn's test. Results: In both experimental models changes of a similar nature in the expression of Notch pathway components were found. Androgen deprivation caused the reduction of mRNA and protein expression of DLL4 ligand, activated forms of Notch1 and Notch2 receptors and HES1 and HEY1 effector genes (p < 0.05, p < 0.01, p < 0.001). In contrast, DLL1, JAG1 and HES5 expressions increased in seminiferous epithelium of both flutamide and EDS-treated rats (p < 0.05, p < 0.01, p < 0.001). Conclusions: Androgens and androgen receptor signaling may be considered as factors regulating Notch pathway activity and the expression of Hes and Hey genes in rat seminiferous epithelium during pubertal development. Further studies should focus on functional significance of androgen-Notch signaling cross-talk in the initiation and maintenance of spermatogenesis.

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Section: Discussionmentioning

confidence: 99%

Disruption of androgen signaling during puberty affects Notch pathway in rat seminiferous epithelium

Kamińska

Marek

Pardyak

et al. 2020

Reprod Biol Endocrinol

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“…Interestingly, NOTCH2, a NOTCH receptor important during Leydig cell differentiation 48 , is a target gene of some of the downregulated miRNAs (hsa-mir-16-5p, hsamir-17-5p, hsa-mir-92a-3p, hsa-mir-106a-5p, hsa-mir-181a-5p, hsa-mir-15b-5p, and hsa-mir-23b-3p). www.nature.com/scientificreports/ ERBB2 encodes an epidermal growth factor tyrosine kinase that does not have its own ligand-binding domain and therefore does not bind to growth factors; however, it binds strongly to other members of the EGF receptor family to form heterodimers that stabilize ligand binding and increase the kinase-mediated activation of signalling pathways 47,49 . ERBB2 and ERBB3 were detected in undifferentiated type A spermatogonia and in a rat spermatogonial stem cell line.…”

Section: Discussionmentioning

confidence: 99%

“…A separate study indicated that germ cells in mouse testes induce the activation of Notch in Sertoli cells through Jag1 and trigger their own differentiation through the negative regulation of Cyp26b1. When germ cells do not produce functional Jag1, the Notch pathway is not activated, and the germ cells remain in an undifferentiated state 47 . Interestingly, NOTCH2, a NOTCH receptor important during Leydig cell differentiation 48 , is a target gene of some of the downregulated miRNAs (hsa-mir-16-5p, hsa-mir-17-5p, hsa-mir-92a-3p, hsa-mir-106a-5p, hsa-mir-181a-5p, hsa-mir-15b-5p, and hsa-mir-23b-3p).…”

Section: Discussionmentioning

confidence: 99%

Expression profile of microRNAs in the testes of patients with Klinefelter syndrome

Ibarra‐Ramírez

Calvo-Anguiano

Lugo-Trampe

et al. 2020

Sci Rep

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Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy. A distinctive characteristic of KS is oligozoospermia. Despite multiple studies that have described the natural history of the degenerative process of germ cells in patients with KS, the molecular mechanisms that initiate this process are not well characterized. MicroRNA (miRNA)-mediated post-transcriptional control mechanisms have been increasingly recognized as important regulators of spermatogenesis; however, only a few studies have evaluated the role of miRNAs in the gonadal failure of these patients. Here, we describe a differential expression profile for the miRNAs in testicular tissue samples taken from KS patients. We analysed testicular tissue samples from 4 KS patients and 5 control patients (obstructive azoospermia) through next-generation sequencing, which can provide information about the mechanisms involved in the degeneration of germ cells. A distinctive differential expression profile was identified for 166 miRNAs in the KS patients: 66 were upregulated, and 100 were downregulated. An interactome analysis was performed for 7 of the upregulated and the 20 downregulated miRNAs. The results showed that the target genes are involved in the development, proliferation, and differentiation processes of spermatogenesis, which may explain their role in the development of infertility. This is the first report of a miRNA expression profile generated from testicular tissue samples of KS patients. Klinefelter syndrome (KS) is the most common sex chromosome aneuploidy in humans, with a prevalence of 1:500 live births 1. It was first described in 1942 as a syndrome characterized by gynaecomastia, azoospermia, and elevated levels of follicle-stimulating hormone (FSH) 2. The presence of an extra X chromosome (47,XXY) in the standard male chromosome set (46,XY) causes Klinefelter syndrome. Chromosomal nondisjunction during meiosis or early embryonic mitosis causes this aneuploidy. Cytogenetic confirmation of aneuploidy is performed through conventional karyotype analysis. Approximately 85-90% of KS patients present with a 47,XXY chromosome set, while the remaining 10-15% of patients present with mosaicism (47,XXY/46,XY) or aneuploidies with more than three sex chromosomes (48,XXXY or 48,XXYY) 3,4. Sexual development in KS patients may be healthy before puberty, showing typical pubertal changes and levels of luteinizing hormone (LH), FSH, and testosterone 5. During adolescence, the testicles appear small and firm and the patient presents with multiple symptoms of androgen deficiency. Hypogonadotropic hypogonadism (HH) is the predominant characteristic, with testosterone levels below 12 nmol/L; low levels of insulin-like 3 (INSL 3), inhibin B and anti-Müllerian hormone (AMH); and high levels of FSH and LH 6. Infertility is one of the distinctive characteristics of KS, found in approximately 10% of azoospermia patients. During puberty, the testicles of KS patients grow to a volume of 6 ml; however, although the serum levels of testosterone increas...

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“…Thus, RA concentration in stages II-VI might be kept low, even in the presence of Aldh1a1. Moreover, the CYP26 family of enzymes, which are expressed in Sertoli cells [60,170,173,174], may catabolize RA to maintain tight control of the seminiferous milieu.…”

Section: Periodicity Of Spermatogenesis and Ra Levelsmentioning

confidence: 99%

Retinoic Acid and Germ Cell Development in the Ovary and Testis

et al. 2019

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Retinoic acid (RA), a derivative of vitamin A, is critical for the production of oocytes and sperm in mammals. These gametes derive from primordial germ cells, which colonize the nascent gonad, and later undertake sexual differentiation to produce oocytes or sperm. During fetal development, germ cells in the ovary initiate meiosis in response to RA, whereas those in the testis do not yet initiate meiosis, as they are insulated from RA, and undergo cell cycle arrest. After birth, male germ cells resume proliferation and undergo a transition to spermatogonia, which are destined to develop into haploid spermatozoa via spermatogenesis. Recent findings indicate that RA levels change periodically in adult testes to direct not only meiotic initiation, but also other key developmental transitions to ensure that spermatogenesis is precisely organized for the prodigious output of sperm. This review focuses on how female and male germ cells develop in the ovary and testis, respectively, and the role of RA in this process.

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Undifferentiated spermatogonia regulateCyp26b1expression through NOTCH signaling and drive germ cell differentiation

Cited by 26 publications

References 69 publications

Disruption of androgen signaling during puberty affects Notch pathway in rat seminiferous epithelium

Disruption of androgen signaling during puberty affects Notch pathway in rat seminiferous epithelium

Expression profile of microRNAs in the testes of patients with Klinefelter syndrome

Retinoic Acid and Germ Cell Development in the Ovary and Testis

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