Anchoring Junctions As Drug Targets: Role in Contraceptive Development

Mruk, Dolores D.; Silvestrini, Bruno; Cheng, C. Yan

doi:10.1124/pr.107.07105

Cited by 128 publications

(175 citation statements)

References 529 publications

(603 reference statements)

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“…2,12,15,16 At the early stage of the epithelial cycle, the disassembly and reassembly of the basal ES-BTB is necessary for the transit of preleptotene spermatocytes across the BTB to enter the apical compartment and prepare for meiosis. 2,16,17 After spermatocytes enter the apical compartment, the apical ES replaces the desmosome-like junctions and gap junctions in the Sertoligerm cell interface and persists until the spermatids line up at the luminal edge of the seminiferous tubule. The apical ES disassembly facilitates the release of spermatozoa during spermiation.…”

Section: Introductionmentioning

confidence: 99%

“…The apical ES disassembly facilitates the release of spermatozoa during spermiation. 6,17,18 Both basal and apical ES undergo recycling at the late stages of the epithelial cycle so that the ES proteins can be endocytosed, transcytosed and recycled to assemble new apical and basal ES. 9,19 The extensive restructuring of basal and apical ES is crucial to spermatogenesis, and recent studies have shown many molecules and signaling pathways participate in ES restructuring.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy is required for ectoplasmic specialization assembly in sertoli cells

et al. 2016

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The ectoplasmic specialization (ES) is essential for Sertoli-germ cell communication to support all phases of germ cell development and maturity. Its formation and remodeling requires rapid reorganization of the cytoskeleton. However, the molecular mechanism underlying the regulation of ES assembly is still largely unknown. Here, we show that Sertoli cell-specific disruption of autophagy influenced male mouse fertility due to the resulting disorganized seminiferous tubules and spermatozoa with malformed heads. In autophagy-deficient mouse testes, cytoskeleton structures were disordered and ES assembly was disrupted. The disorganization of the cytoskeleton structures might be caused by the accumulation of a negative cytoskeleton organization regulator, PDLIM1, and these defects could be partially rescued by Pdlim1 knockdown in autophagy-deficient Sertoli cells. Altogether, our works reveal that the degradation of PDLIM1 by autophagy in Sertoli cells is important for the proper assembly of the ES, and these findings define a novel role for autophagy in Sertoli cell-germ cell communication.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy is required for ectoplasmic specialization assembly in sertoli cells

et al. 2016

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“…33 It is noted that the apical ES is an F-actin-rich testis-specific adherens junction, in which bundles of actin filaments that lie perpendicular to the plasma membrane of the Sertoli cell are sandwiched between cisternae of endoplasmic reticulum and the apposing Sertoli-spermatid plasma membrane. 14,46,56 Once the apical ES appears in step 8 spermatids during spermiogenesis, it is the only anchoring device, replacing desmosomes and gap junctions. It persists until step 19 spermatids when mature spermatozoa are released into the tubule lumen at spermiation.…”

Section: Bcrp and Spermatogenesis Xj Qian Et Al 457mentioning

confidence: 99%

“…Our interest in studying drug transporters stems from our investigation of developing adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, into a male contraceptive. [13][14][15] Although this compound is highly potent at disrupting germ cell adhesion in the testes, the drug was shown to have very limited bioavailability following oral administration. 16 Success in developing this compound into a male contraceptive relies heavily on our ability to prepare a better formulated version that is both economical to manufacture and that requires a low efficacy dose.…”

Section: Introductionmentioning

confidence: 99%

“…14,25 Bcrp displays a restrictive spatiotemporal pattern of expression during the epithelial cycle, such that it is only detected at the apical ES in stage VI-VIII tubules, but not at stage IX-XIV or I-V (Figure 3). 33 In short, unlike other drug transporters, such as P-glycoprotein and Oatp3, 34,35 Bcrp is not a component of the Sertoli cell BTB, 33 but is stage specifically expressed by Sertoli cells and spermatid in addition to abundant expression by endothelial cells and peritubular myoid cells in rat testes.…”

Section: Introductionmentioning

confidence: 99%

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Breast cancer resistance protein (Bcrp) and the testis—an unexpected turn of events

Qian¹,

Cheng²,

Mruk³

et al. 2013

Asian J Androl

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Breast cancer resistance protein (Bcrp) is an ATP-dependent efflux drug transporter. It has a diverse spectrum of hydrophilic and hydrophobic substrates ranging from anticancer, antiviral and antihypertensive drugs, to organic anions, antibiotics, phytoestrogens (e.g., genistein, daidzein, coumestrol), xenoestrogens and steroids (e.g., dehydroepiandrosterone sulfate). Bcrp is an integral membrane protein in cancer and normal cells within multiple organs (e.g., brain, placenta, intestine and testis) that maintains cellular homeostasis by extruding drugs and harmful substances from the inside of cells. In the brain, Bcrp is a major component of the bloodbrain barrier located on endothelial cells near tight junctions (TJs). However, Bcrp is absent at the Sertoli cell blood-testis barrier (BTB); instead, it is localized almost exclusively to the endothelial TJ in microvessels in the interstitium and the peritubular myoid cells in the tunica propria. Recent studies have shown that Bcrp is also expressed stage specifically and spatiotemporally by Sertoli and germ cells in the seminiferous epithelium of rat testes, limited only to a testis-specific cell adhesion ultrastructure known as the apical ectoplasmic specialisation (ES) in stage VI-early VIII tubules. These findings suggest that Bcrp is equipped by late spermatids and Sertoli cells to protect late-stage spermatids completing spermiogenesis. Furthermore, Bcrp was found to be associated with F (filamentous)-actin and several actin regulatory proteins at the apical ES and might be involved in the organisation of actin filaments at the apical ES in stage VII-VIII tubules. These findings will be carefully evaluated in this brief review.

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Targeted disruption of the spermatid‐specific gene Spata31 causes male infertility

Yang

et al. 2015

Molecular Reproduction Devel

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Spata31, a novel testis-specific gene, was first isolated from the testis of a vitamin A-deficient rat model. To gain insight into its physiological function, Spata31-targeted knockout mice were generated by homologous recombination. Spata31-deficient (Spata31(flox/flox) ; Vasa-Cre) male mice exhibited low sperm count and premature shedding of germ cells into the lumen, ultimately causing azoospermia and male sterility. Mechanistically, the Spata31 deficiency resulted in reduced expression of the adhesion protein nectin-3 and cytoskeletal protein β-actin at the apical ectoplasmic specialization. Our findings demonstrate that the disruptions to the SPATA31 ortholog could be linked to human male infertility.

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Anchoring Junctions As Drug Targets: Role in Contraceptive Development

Cited by 128 publications

References 529 publications

Autophagy is required for ectoplasmic specialization assembly in sertoli cells

Autophagy is required for ectoplasmic specialization assembly in sertoli cells

Breast cancer resistance protein (Bcrp) and the testis—an unexpected turn of events

Targeted disruption of the spermatid‐specific gene Spata31 causes male infertility

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