Analysis of transcript and methylation levels of INSL3 and RXFP2 in undescended and descended dog testes suggested promising biomarkers associated with cryptorchidism

Nowacka‐Woszuk, Joanna; Krzemińska, Paulina; Nowak, Tomasz; Gogulski, Maciej; Świtoński, M.; Stachowiak, Monika

doi:10.1016/j.theriogenology.2020.08.029

Cited by 10 publications

(15 citation statements)

References 33 publications

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“…The results of our study showed that mouse gubernacular cells could be specifically labeled by the goat anti-mouse RXFP2 polyclonal antibody, which proved that RXFP2 was involved in the structure of the gubernacular cell membrane. INSL3 binds to the specific receptor RXFP2 located on the cell membrane to form the INSL3/RXFP2 complex, which then produces biological effects, stimulates the proliferation of the gubernaculum, and regulates the growth and development of the gubernaculum [ 8 , 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

The RXFP2-PLC/PKC signaling pathway mediates INSL3-induced regulation of the proliferation, migration and apoptosis of mouse gubernacular cells

Duan

Jiang

et al. 2023

Cell Mol Biol Lett

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Background Testicular hypoplasia can affect the sexual and reproductive ability in adulthood, and even increase the risk of cancer. Abnormal development of the gubernaculum is one of the important factors of testicular hypoplasia. Therefore, a study of the structure and function of the gubernaculum is an important but neglected new breakthrough point for investigating the normal/abnormal development of the testis. Previous findings showed that Insulin like factor 3 (INSL3) is a key factor regulating the growth of gubernaculum, however, the mechanism by which INSL3 acts on the gubernaculum remains unknown. Therefore, we probed the mechanism associated with INSL3-induced the proliferation, migration, and apoptosis of gubernacular cells in mice. Methods A culture cell model of neonatal mice gubernaculum is established by INSL3 intervention. We blocked PLC/PKC signaling pathway with U73122 pretreat to investigate the role of the PLC/PKC signaling pathway. The changes of cell proliferation, migration, and apoptosis were detected by molecular biological methods. In addition, the levels of PCNA and F-action were detected by immunofluorescence and western blotting. Results We found that INSL3 can promote the proliferation and migration of gubernacular cells and inhibit their apoptosis, meanwhile, INSL3 significantly up-regulated PLC/PKC protein phosphorylation. However, treatment with the PLC/PKC signaling pathway inhibitor U73122 significantly inhibited these effects of INSL3. Besides, we found that INSL3 could up-regulate the protein expression level of PCNA and F-actin, while the PCNA and F-actin expression was significantly weakened after U73122 pretreatment. Conclusions This research revealed that INSL3 binding to RXFP2 may up-regulate the expression levels of PCNA and F-actin by activating the PLC/PKC signaling pathway to promote the proliferation and migration of gubernacular cells. It suggests that the RXFP2-PLC/PKC axis may serve as a novel molecular mechanism by which INSL3 regulates growth of the gubernaculum.

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Section: Discussionmentioning

confidence: 99%

The RXFP2-PLC/PKC signaling pathway mediates INSL3-induced regulation of the proliferation, migration and apoptosis of mouse gubernacular cells

Duan

Jiang

et al. 2023

Cell Mol Biol Lett

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“…Multiple mutations have been researched to explain the implication of INSL3 and its specific receptor, RXFP2, in boys with undescended testis. As stated by Nowacka-Woszuk et al [ 14 ], the frequency of INSL3 mutation is 1–2%, and RXFP mutation–2–4%, although numerous polymorphisms have also been described. This observation led to the suggestion that genetic mutations are mostly seen in the bilateral cases of undescended testes.…”

Section: Discussionmentioning

confidence: 99%

New Insights into the Role of INSL-3 in the Development of Cryptorchidism

et al. 2023

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Cryptorchidism, defined as the failure of at least one or both testicles to descend into the scrotal pouches, is the most frequent (1.6–9% at birth, 1/20 males at birth) congenital anomaly encountered in newborn males, resulting in one of the most frequent causes of non-obstructive azoospermia in men. Similar to other congenital malformations, cryptorchidism is thought to be caused by endocrine and genetic factors, combined with maternal and environmental influences. The etiology of cryptorchidism is unknown, as it involves complex mechanisms aiming to control the testicular development and descent from their initial intra-abdominal location in scrotal pouches. The implication of insulin-like 3 (INSL-3) associated with its receptor (LGR8) is critical. Genetic analysis discloses functionally deleterious mutations in INSL3 and GREAT/LGR8 genes. In this literature review, we discuss and analyze the implication of INSL3 and the INSL3/LGR8 mutation in the occurrence of cryptorchidism in both human and animal models.

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“…FLc also secretes INSL3, a member of the insulin-relaxin family of peptides that acts on the body through the G-protein-coupled receptor relaxin/insulin-like family peptide receptor 2 (RXFP2). Missense mutations or ablation of Insl3 or Rxfp2 causes cryptorchidism leading to azoospermia (87,88). However, unlike rodents, primate Lc shows a triphasic developmental pattern (83-86).…”

Section: Target Cellsmentioning

confidence: 99%

Revisiting the gonadotropic regulation of mammalian spermatogenesis: evolving lessons during the past decade

2023

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Spermatogenesis is a multi-step process of male germ cell (Gc) division and differentiation which occurs in the seminiferous tubules of the testes under the regulation of gonadotropins – Follicle Stimulating Hormone (FSH) and Luteinising hormone (LH). It is a highly coordinated event regulated by the surrounding somatic testicular cells such as the Sertoli cells (Sc), Leydig cells (Lc), and Peritubular myoid cells (PTc). FSH targets Sc and supports the expansion and differentiation of pre-meiotic Gc, whereas, LH operates via Lc to produce Testosterone (T), the testicular androgen. T acts on all somatic cells e.g.- Lc, PTc and Sc, and promotes the blood-testis barrier (BTB) formation, completion of Gc meiosis, and spermiation. Studies with hypophysectomised or chemically ablated animal models and hypogonadal (hpg) mice supplemented with gonadotropins to genetically manipulated mouse models have revealed the selective and synergistic role(s) of hormones in regulating male fertility. We here have briefly summarized the present concept of hormonal control of spermatogenesis in rodents and primates. We also have highlighted some of the key critical questions yet to be answered in the field of male reproductive health which might have potential implications for infertility and contraceptive research in the future.

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Analysis of transcript and methylation levels of INSL3 and RXFP2 in undescended and descended dog testes suggested promising biomarkers associated with cryptorchidism

Cited by 10 publications

References 33 publications

The RXFP2-PLC/PKC signaling pathway mediates INSL3-induced regulation of the proliferation, migration and apoptosis of mouse gubernacular cells

The RXFP2-PLC/PKC signaling pathway mediates INSL3-induced regulation of the proliferation, migration and apoptosis of mouse gubernacular cells

New Insights into the Role of INSL-3 in the Development of Cryptorchidism

Revisiting the gonadotropic regulation of mammalian spermatogenesis: evolving lessons during the past decade

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