Physiological roles of connexins and pannexins in reproductive organs

Kibschull, Mark; Gellhaus, Alexandra; Carette, Diane; Segretain, Dominique; Pointis, Georges; Gilleron, Jérôme

doi:10.1007/s00018-015-1965-4

Cited by 23 publications

(17 citation statements)

References 187 publications

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“…Small metabolites conveyed through gap junctions but also channel-independent effector functions of the cytosolic C-terminal domain (CT) of Cxs control crucial cell processes, including cell growth, in physiology and disease (Naus and Laird, 2010; Kibschull et al, 2015; Leithe et al, 2018). Tissue ischemia activates a cascade of vasodilatory, inflammatory and remodeling processes and endothelial Cxs are increasingly recognized to orchestrate these events.…”

Section: Discussionmentioning

confidence: 99%

KLF4-Induced Connexin40 Expression Contributes to Arterial Endothelial Quiescence

et al. 2019

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Shear stress, a blood flow-induced frictional force, is essential in the control of endothelial cell (EC) homeostasis. High laminar shear stress (HLSS), as observed in straight parts of arteries, assures a quiescent non-activated endothelium through the induction of Krüppel-like transcription factors (KLFs). Connexin40 (Cx40)-mediated gap junctional communication is known to contribute to a healthy endothelium by propagating anti-inflammatory signals between ECs, however, the molecular basis of the transcriptional regulation of Cx40 as well as its downstream effectors remain poorly understood. Here, we show that flow-induced KLF4 regulated Cx40 expression in a mouse EC line. Chromatin immunoprecipitation in ECs revealed that KLF4 bound to three predicted KLF consensus binding sites in the Cx40 promoter. HLSS-dependent induction of Cx40 expression was confirmed in primary human ECs. The downstream effects of Cx40 modulation in ECs exposed to HLSS were elucidated by an unbiased transcriptomics approach. Cell cycle progression was identified as an important downstream target of Cx40 under HLSS. In agreement, an increase in the proportion of proliferating cell nuclear antigen (PCNA)-positive ECs and a decrease in the proportion of ECs in the G0/G1 phase were observed under HLSS after Cx40 silencing. Transfection of communication-incompetent HeLa cells with Cx40 demonstrated that the regulation of proliferation by Cx40 was not limited to ECs. Using a zebrafish model, we finally showed faster intersegmental vessel growth and branching into the dorsal longitudinal anastomotic vessel in embryos knock-out for the Cx40 orthologs Cx41.8 and Cx45.6 . Most significant effects were observed in embryos with a mutant Cx41.8 encoding for a channel with reduced gap junctional function. Faster intersegmental vessel growth in Cx41.8 mutant embryos was associated with increased EC proliferation as assessed by PH3 immunostaining. Our data shows a novel evolutionary-conserved role of flow-driven KLF4-dependent Cx40 expression in endothelial quiescence that may be relevant for the control of atherosclerosis and diseases involving sprouting angiogenesis.

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Section: Discussionmentioning

confidence: 99%

KLF4-Induced Connexin40 Expression Contributes to Arterial Endothelial Quiescence

et al. 2019

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“…Several lines of evidence indicate that not only TJ but also GJ are required for adequate functioning of the testis. In adult male, connexin 43 (Cx43), the most abundant testicular GJ protein is predominantly localized at the region of BTB and among Leydig cells within the interstitial tissue [ 5 , 6 ]. Studies on Sertoli cell-specific deletion of Cx43 revealed that this connexin is an absolute requirement for the Sertoli cell development and initiation of spermatogenesis [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Flutamide induces alterations in the cell-cell junction ultrastructure and reduces the expression of Cx43 at the blood-testis barrier with no disturbance in the rat seminiferous tubule morphology

Chojnacka

Hejmej

Zarzycka

et al. 2016

Reprod Biol Endocrinol

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BackgroundPresent study was designed to establish a causal connection between changes in the cell-cell junction protein expression at the blood-testis barrier and alterations in the adult rat testis histology following an anti-androgen flutamide exposure. Particular emphasis was placed on the basal ectoplasmic specialization (ES) in the seminiferous epithelium and expression of gap junction protein, connexin 43 (Cx43).MethodsFlutamide (50 mg/kg body weight) was administered to male rats daily from 82 to 88 postnatal day. Testes from 90-day-old control and flutamide-exposed rats were used for all analyses. Testis morphology was analyzed using light and electron microscopy. Gene and protein expressions were analyzed by real-time RT-PCR and Western blotting, respectively, protein distribution by immunohistochemistry, and steroid hormone concentrations by radioimmunoassay.ResultsSeminiferous epithelium of both groups of rats displayed normal histology without any loss of germ cells. In accord, no difference in the apoptosis and proliferation level was found between control and treated groups. As shown by examination of semi-thin and ultrathin sections, cell surface occupied by the basal ES connecting neighboring Sertoli cells and the number of gap and tight junctions coexisting with the basal ES were apparently reduced in flutamide-treated rats. Moreover, the appearance of unconventional circular ES suggests enhanced internalization and degradation of the basal ES. These changes were accompanied by decreased Cx43 and ZO-1 expression (p < 0.01) and a loss of linear distribution of these proteins at the region of the blood-testis barrier. On the other hand, Cx43 expression in the interstitial tissue of flutamide-treated rats increased (p < 0.01), which could be associated with Leydig cell hypertrophy. Concomitantly, both intratesticular testosterone and estradiol concentrations were elevated (p < 0.01), but testosterone to estradiol ratio decreased significantly (p < 0.05) in flutamide-treated rats compared to the controls.ConclusionsShort-term treatment with flutamide applied to adult rats exerts its primary effect on the basal ES, coexisting junctional complexes and their constituent proteins Cx43 and ZO-1, without any apparent morphological alterations in the seminiferous epithelium. In the interstitial compartment, however, short-term exposure leads to both histological and functional changes of the Leydig cells.

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“…Various types of connexins are expressed in the mammalian female reproductive system, which plays an important role in its physiology. Cx43 and Cx37 are predominantly expressed in the ovarian follicles of humans and mice [12]. In both mice and humans, Cx43 forms gap junctions that connect granulosa cells [13,14].…”

Section: Wwwbjbmsorgmentioning

confidence: 99%

“…In both mice and humans, Cx43 forms gap junctions that connect granulosa cells [ 13 , 14 ]. In mice, Cx37 connects oocytes with the surrounding cumulus cells; while in humans, the location of Cx37 in the granulosa cells of fertile women is not clear [ 12 ]. In the endometrium in both rats and humans, Cx26 and Cx43 are the two major connexins [ 15 - 17 ].…”

Section: Introductionmentioning

confidence: 99%

Androgen effect on connexin expression in the mammalian female reproductive system: a systematic review

Kamal

Ibrahim

Mokhtar

2019

Bosn J of Basic Med Sci

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The functions of androgen and connexin in the mammalian female reproductive system are suggested to be related. Previous research has shown that androgen affects connexin expression and localization in the female reproductive system, altering its function. However, no definitive conclusion on their cause-effect relationship has been drawn yet. In addition, a high prevalence of women with polycystic ovary syndrome (PCOS), who are characterized by elevated androgen levels and failure of ovulation, has prompted the studies on the relationship between androgen and connexin in the ovaries. This systematic review aims to investigate the effect of androgen on connexin expression in the mammalian female reproductive system. The literature search was conducted using the MEDLINE, EBSCOhost, and Scopus databases and the following keywords: “androgen” or “testosterone” or “androgen blocker” or “anti-androgen” or “androstenedione” or “dehydroepiandrosterone” or “flutamide AND connexin” or “gap junction” or “cell junction”. We only considered in vitro and in vivo studies that involved treatment by androgen or androgen receptor blockers and measured connexin expression as one of the parameters. Our review showed that the exposure to androgen or androgen blocker affects connexin expression but not its localization in the mammalian ovary. However, it is not clear whether androgen downregulates or upregulates connexin expression. Additionally, it is inconclusive whether the upregulation of connexin positively contributes to the ovarian function.

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Physiological roles of connexins and pannexins in reproductive organs

Cited by 23 publications

References 187 publications

KLF4-Induced Connexin40 Expression Contributes to Arterial Endothelial Quiescence

KLF4-Induced Connexin40 Expression Contributes to Arterial Endothelial Quiescence

Flutamide induces alterations in the cell-cell junction ultrastructure and reduces the expression of Cx43 at the blood-testis barrier with no disturbance in the rat seminiferous tubule morphology

Androgen effect on connexin expression in the mammalian female reproductive system: a systematic review

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