Memeli Testisinde Kan-Testis Bariyeri’nin Bileşenleri ve Üreme ile İlişkileri

Year 2023, , 141 - 151, 01.08.2023

Betül Fidan Narin Liman

https://doi.org/10.32707/ercivet.1332031

Abstract

Memelilerde vücudun bazı özel bölümlerindeki molleküllerin kan ve dokular arasındaki hareketi “kan-doku bariyeri” adı verilen yapılar tarafından kontrol edilir. Bu bariyerlerin başlıcaları kan-beyin, -plasenta, -retina, -timus, -testis ve - epididimis bariyerleridir. Kan-testis bariyeri (BTB) ve kan-epididimis bariyeri (BEB) erkek üreme sistemindeki iki önemli hücresel bariyerdir. Seminifer epitelde yerleşen ve komşu Sertoli hücreleri arasında bulunan BTB, tight junction, gap junction (geçit bağlantıları), desmozom (macula adherens) ve adherens junction (bazal ektoplazmik özelleşme-testise özgü bir yapışma bağlantısı) tipi bağlantılar tarafından oluşturulur. Bu bariyer gelişmekte olan germ hücrelerini, özellikle postmayotik spermatidleri, kan ve lenf yoluyla buraya taşınan zararlı ajanlardan (ilaçlar, toksik kimyasallar ve mutajen- ler gibi) koruyan ve farklılaşmış germ hücrelerine karşı oluşabilecek otoimmun tepkileri önleyen biyokimyasal ve immünolojik bir mikro çevre oluşturur. BTB seminifer tübül epitelini bazal ve adluminal bölmelere ayırarak hücre polaritesi sağlar ve tübül lümenindeki sıvının kimyasal bileşiminin korunmasına yardımcı olur. BTB spermatogenez sırasında yeniden yapılanmaya uğrar, ancak bütünlüğü bozulmaz. Böylece germ hücreleri bu benzersiz yapı sayesinde seminifer epitel boyunca taşınır. Bariyeri oluşturan bileşenlerden herhangi birinde bozulma olması durumunda germ hücreleri gelişimlerini tamamlayamaz ve erkeklerde infertilite şekillenir. Ayrıca, gelişmemiş germ hücreleri sekonder oositi dölle- yemediğinden dişi fertilitesi de dolaylı olarak bu durumdan etkilenebilir. Özetle bu bariyer germ hücrelerinin hayatta kalması ve normal spermatogenezin devamlılığı için kritik bir öneme sahiptir. Bu derlemenin amacı, memelilerde erkek infertilitesinde önemli rol oynayan kan-testis bariyerini oluşturan bağlantı komplekslerinin moleküler bileşenleri hakkında bilgi vermektir.

Keywords

Kan-testis bariyeri, sıkı bağlantılar, testis, tutundurucu bağlantılar

Components of the Blood-Testis Barrier in the Mammalian Testis and Their Relationship with Fertility

Abstract

In some special parts of the mammalian body, the movement of molecules between blood and tissues is controlled by structures called “blood-tissue barriers.” These barriers are mainly the blood-brain, -placenta, -retina, - thymus, -testis, and -epididymis barriers. The blood-testis barrier (BTB) and the blood-epididymis barrier (BEB) are the two important cellular barriers in the male reproductive system. BTB is localized between adjacent Sertoli cells in the seminiferous epithelium of the testis and is formed by tight junctions, GAP junctions, desmosomes (macula adherens), and adherens junctions (ectoplasmic specialization-a testis-specific adhesion junction). The BTB creates a biochemical and immunological microenvironment that protects developing germ cells, especially post-meiotic spermatids, from harmful agents (such as drugs, toxic chemicals, and mutagens) carried there by blood and lymph and that prevents autoimmune responses against differentiated germ cells. The BTB divides the seminiferous tubule epithelium into basal and adluminal compartments, ensuring cell polarity and helping to maintain the chemical composition of the fluid in the tubule lumen. BTB undergoes remodeling during spermatogenesis, but its integrity remains intact. Thus, thanks to this unique structure, the germ cells are transported across the seminiferous epithelium. Any disruption in the components that make up the barrier can adversely affect Sertoli-germ cell interactions, preventing germ cells from completing their development and leading to male infertility. In addition, female fertility may be indirectly affected as immature germ cells cannot fertilize the secondary oocyte. In summary, this barrier is critical for germ cell survival and maintenance of normal spermatogenesis. This review aims to provide information about the molecular components of the junction complexes that form the blood-testis barrier, which plays an important role in male infertility in mammals.

Keywords

Adherens junction, blood-testis barrier, testis, tight junction

References

• Agarwal A, Saleh RA, Bedaiwy MA. Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil Steril 2003; 79(4): 829-43.
• Amasheh S, Milatz S, Krug SM, Markov AG, Günzel D, Amasheh M, Fromm M. Tight junction proteins as channel formers and barrier builders. Ann N Y Acad Sci 2009; 1165: 211-9.
• Cheng CY, Silvestrini B, Grima J, Mo M, Zhu L, Jo- hansson E, Leone M, Palmery M, Mruk D. Two new male contraceptives exert their effects by depleting germ cells prematurely from the tes- tis. Biol Reprod 2001; 65(2): 449-61.
• Cheng CY, Mruk DD. Cell junction dynamics in the testis: Sertoli-germ cell interactions and male contraceptive development. Physiol Rev 2002; 82 (4): 825-74.
• Cheng CY, Mruk DD. An intracellular trafficking pathway in the seminiferous epithelium regulating spermatogenesis: A biochemical and molecular perspective. Crit Rev Biochem Mol Biol 2009; 44 (5): 245-63.
• Cheng CY, Mruk DD. A local autocrine axis in the testes that regulates spermatogenesis. Nat Rev Endocrinol 2010; 6(7): 380-95.
• Cheng CY, Wong EW, Lie PP, Li MW, Mruk DD, Yan HH, Mok KW, Mannu J, Mathur PP, Lui WY, Lee WM, Bonanomi M, Silvestrini B. Regulation of blood-testis barrier dynamics by desmosome, gap junction, hemidesmosome and polarity proteins: An unexpected turn of events. Spermatogenesis 2011; 1(2): 105-15.
• Chung NP, Cheng CY. Is cadmium chloride-induced inter-Sertoli tight junction permeability barrier disruption a suitable in vitro model to study the events of junction disassembly during spermato- genesis in the rat testis? Endocrinology 2001; 142 (5): 1878-88.
• Domke LM, Rickelt S, Dörflinger Y, Kuhn C, Winter- Simanowski S, Zimbelmann R, Rosin-Arbesfeld R, Heid H, Franke WW. The cell-cell junctions of mammalian testes: I. The adhering junctions of the seminiferous epithelium represent special differentiation structures. Cell Tissue Res 2014; 357(3): 645-65.
• Ebnet K. Junctional adhesion molecules (JAMs): Cell adhesion receptors with pleiotropic functions in cell Physiology and Development. Physiol Rev 2017; 97(4): 1529-54.
• Fiorini C, Tilloy-Ellul A, Chevalier S, Charuel C, Poin- tis G. Sertoli cell junctional proteins as early tar- gets for different classes of reproductive toxi- cants. Reprod Toxicol 2004; 18(3): 413-21.
• Garrido-Urbani S, Bradfield PF, Imhof BA. Tight junction dynamics: The role of junctional adhesion molecules (JAMs). Cell Tissue Res 2014; 355(3): 701-15.
• Gerber J, Heinrich J, Brehm R. Blood-testis barrier and Sertoli cell function: Lessons from SCCx43KO mice. Reproduction 2016; 151(2): R15-27.
• González-Mariscal L, Betanzos A, Avila-Flores A. MAGUK proteins: Structure and role in the tight junction. Semin Cell Dev Biol 2000;11(4): 315-24.
• Gram DY, Sexton B, Liman N, Müller L, Abay M, Gram A, Balogh O. Testicular expression of anti-oxidant enzymes and changes in response to a slow-release Deslorelin implant (Suprelorin® 4,7 mg) in the Dog. Animals, 2022; 12(18): 2343.
• Gurel C, Kuscu GC, Buhur A, Dagdeviren M, Oltulu F, Karabay Yavasoglu NU, Yavasoglu A. Fluvas- tatin attenuates doxorubicin-induced testicular toxicity in rats by reducing oxidative stress and regulating the blood-testis barrier via mTOR sig- naling pathway. Hum Exp Toxicol 2019; 38(12): 1329-43.
• Günzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev 2013; 93 (2): 525-69.
• Hartmann C, Schwietzer YA, Otani T, Furuse M, Eb- net K. Physiological functions of junctional adhe- sion molecules (JAMs) in tight junctions. Biochim Biophys Acta Biomembr 2020; 1862(9): 183299.
• Hatzfeld M. Plakophilins: Multifunctional proteins or just regulators of desmosomal adhesion? BiochimBiophys Acta 2007; 1773(1): 69-77.
• Hess RA, Renato de Franca L. Spermatogenesis and cycle of the seminiferous epithelium. Adv Exp Med Biol 2008; 636: 1-15.
• Johnson L. Efficiency of spermatogenesis. Micros Res Techn 1995; 32(5): 385-422.
• Johnson KJ, Boekelheide K. Dynamic testicular ad- hesion junctions are immunologically unique. II. Localization of classic cadherins in rat testis. Biol Reprod 2002; 66(4): 992-1000.
• Kaur G, Mital P, Dufour JM. Testisimmune privilege- assumptions versus facts. Anim Reprod 2013; 10 (1): 3-15.
• Kopera IA, Bilinska B, Cheng CY, Mruk DD. Sertoli– germ cell junctions in the testis: a review of recent data. Philosophical transactions of the royal soci- ety B: Biol Sci 2010; 365(1546): 1593-605.
• Kowalczyk AP, Green KJ. Structure, function, and regulation of desmosomes. Prog Mol Biol Transl Sci 2013; 116: 95-118.
• Kowalczyk AP, Hatzfeld M, Bornslaeger EA, Kopp DS, Borgwardt JE, Corcoran CM, Green KJ. The head domain of plakophilin-1 binds to desmoplakin and enhances its recruitment to desmosomes: implications for cutaneous disease. J Biol Chem 1999; 274(26): 18145-8.
• Kumar NM, Gilula NB. The gap junction communica- tion channel. Cell 1996; 84(3): 381-8.
• Lau AS, Mruk DD. Rab8B GTPase and junction dy- namics in the testis. Endocrinol 2003; 144(4): 1549-63.
• Lee NP, Mruk D, Lee WM, Cheng CY. Is the cadhe- rin/catenin complex a functional unit of cell-cell actin-based adherens junctions in the rat tes- tis? Biol Reprod 2003; 68(2): 489-508.
• Li MW, Mruk DD, Lee WM, Cheng CY. Cytokines and junction restructuring events during spermatoge- nesis in the testis: An emerging concept of regula- tion. Cytokine Growth Factor Rev 2009; 20(4): 329-38.
• Li XY, Zhang Y, Wang XX, Jin C, Wang YQ, Sun TC, Liu YX. (2018). Regulation of blood–testis barrier assembly in vivo by germ cells. FASEB J 2018; 32(3): 1653.
• Lie PPY, Cheng CY, Mruk DD. The desmoglein-2/ desmocollin-2/Src kinase protein complex regula- tes blood-testis barrier dynamics. Int J Biochem Cell Biol 2010; 42: 975-86.
• Lie PP, Cheng CY, Mruk DD. Signalling pathways regulating the blood-testis barrier. Int J Biochem Cell Biol 2013; 45(3): 621-5.
• Liman N, Alan E, Beyaz F, Gürbulak K. Endothelial and inducible nitric oxide synthase (NOS) immu- noreactivity and NOS-associated NADPH- diaphorase histochemistry in the domestic cat (Felis catus) testis. Theriogenology 2013; 80 (9):1017-32.
• Liman N, Ateş N. Abundances and localizations of Claudin-1 and Claudin-5 in the domestic cat (Felis catus) ovary during the estrous cycle. Anim Rep- rod Sci 2020; 212: 106247.
• Liman N. The abundance and localization of claudin- 1 and -5 in the adult tomcats (Felis catus) testis, tubules rectus, rete testis, efferent ductules, and epididymis. Anat Rec (Hoboken) 2023; 1-17.
• Lui WY, Mruk D, Lee WM, Cheng CY. Sertoli cell tight junction dynamics: Their regulation during spermatogenesis. Biol Reprod 2003; 68(4): 1087- 97.
• McMillan M, Andronicos N, Davey R, Stockwell S, Hinch G, Schmoelzl S. Claudin-8 expression in Sertoli cells and putative spermatogonial stem cells in the bovine testis. Reprod Fertil Dev 2014; 26(5): 633-44.
• Mazaud-Guittot S, Meugnier E, Pesenti S, Wu X, Vidal H, Gow A, Le Magueresse-Battistoni B. Cla- udin 11 deficiency in mice results in loss of the Sertoli cell epithelial phenotype in the testis. Biol Reprod 2010; 82(1): 202-13.
• Mineta K, Yamamoto Y, Yamazaki Y, Tanaka H, Ta- da Y, Saito K, Tsukita S. Predicted expansion of the claudin multigene family. FEBS Let 2011; 585 (4): 606-12.
• Mital P, Hinton BT, Dufour JM. The blood-testis and blood-epididymis barriers are more than just their tight junctions. Biol Reprod 2011; 84(5): 851-8.
• Mitic LL, Van ItallieCM, Anderson JM. Molecular phy- siology and pathophysiology of tight junctions I. Tight junction structure and function: Lessons from mutant animals and proteins. Am J Physiol Gastrointest 2000; 279(2): G250-4.
• Mruk DD, Silvestrini B, Mo MY, Cheng CY. Antioxi- dant superoxide dismutase-a review: Its function, regulation in the testis, and role in male ferti- lity. Contraception 2002; 65(4): 305-11.
• Mruk DD, Cheng CY. Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 2004; 25: 747-806.
• Mruk DD, Silvestrini B, Cheng CY. Anchoring juncti- ons as drug targets: Role in contraceptive deve- lopment. Pharmacol Rev 2008; 60(2): 146-80.
• Mruk DD, Cheng CY. The mammalian blood-testis barrier: Its biology and regulation. Endocr Rev 2015; 36(5): 564-91.
• Nagamatsu G, Ohmura M, Mizukami T, Hamaguchi I, Hirabayashi S, Yoshida S, Ohbo K. A CTX family cell adhesion molecule, JAM4, is expressed in stem cell and progenitor cell populations of both male germ cell and hematopoietic cell linea- ges. Mol Cell Biol 2006; 26(22): 8498-506.
• Pellegrini M, Claps G, Orlova VV, Barrios F, Dolci S, Geremia R, Nussenzweig A. Targeted JAM-C deletion in germ cells by Spo11-controlled Cre recombinase. J Cell Sci 2011; 124(1): 91-9.
• Pörtner C, Rode K, Hollenbach J, Thiemeyer H, Be- ineke A, Günzel-Apel AR, Brehm R. Expression of claudin-11 in canine prepubertal testes, and in canine adult testes showing normal spermatoge- nesis, impaired spermatogenesis, or testicular neoplasia. Theriogenology 2020; 148: 122-31.
• Rehder D, Iden S, Nasdala I, Wegener J, Brickwedde MK, Vestweber D, Ebnet K. Junctional adhesion molecule-a participates in the formation of apico- basal polarity through different domains. Exp Cell Res 2006; 312(17): 3389-403.
• Russell L. Desmosome‐like junctions between Sertoli and germ cells in the rat testis. American J Anat 1977; 148(3): 301-12.
• Saito M, Tucker DK, Kohlhorst D, Niessen CM, Kowalczyk AP. Classical and desmosomal cadhe- rins at a glance. J Cell Sci 2012; 125(11): 2547- 52.
• Siu MK, Cheng CY. Interactions of proteases, protease inhibitors, and the β1 integrin/laminin γ3 pro- tein complex in the regulation of ectoplasmic specialization dynamics in the rat testis. Biol Rep- rod 2004; 70(4): 945-64.
• Sonnenberg A and Liem RK. Plakins in development and disease. Exp Cell Res 2007; 313(10): 2189- 203.
• Stammler A, Lüftner BU, Kliesch S, Weidner W, Bergmann M, Middendorff R, Konrad L. Highly conserved testicular localization of claudin-11 in normal and impaired spermatogenesis. PloS one 2016; 11(8): e0160349.
• Stanton PG. Regulation of the blood-testis barrier. Semin Cell Dev Biol 2016; 59: 166-73.
• Takai Y, Nakanishi H. Nectin and afadin: Novel organizers of intercellular junctions. J Cell Sci 2003; 116(1): 17-27.
• Takeshima T, Usui K, Mori K, Asai T, Yasuda K, Ku- roda S, Yumura Y. Oxidative stress and male infertility. Reprod Med Biol 2020; 20(1): 41-52.
• Toyama Y, Maekawa M, Yuasa S. Ectoplasmic speci- alizations in the Sertoli cell: New vistas based on genetic defects and testicular toxicology. Anat Sci Int 2003; 78(1): 1-16.
• Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2001; 2 (4): 285-93.
• Upadhyay RD, Kumar AV, Ganeshan M, Balasinor NH. Tubulobulbar complex: Cytoskeletal remode- ling to release spermatozoa. Reprod Biol Endocri- nol 2012; 10: 27.
• Vogl AW, Pfeiffer DC, Mulholland D, Kimel G, Gutt- man J. Unique and multifunctional adhesion junc- tions in the testis: Ectoplasmic specializations. Arch Histol Cytol 2000; 63: 1-15.
• Wang J, Liu H. The roles of junctional adhesion mole- cules (JAMs) in cell migration. Front Cell Dev Biol 2022; 10: 843671.
• Wolski KM, Perrault C, Tran‐Son‐Tay R, Cameron DF. Strength measurement of the Sertoli‐ spermatid junctional complex. J Androl 2005; 26 (3): 354-9.
• Wong EW, Mruk DD, Cheng CY. Biology and regula- tion of ectoplasmic specialization, an atypical ad- herens junction type, in the testis. Biochim Bi- ophys Acta (BBA)- Biomembr 2008; 1778(3): 692- 708.
• Wong CH, Cheng CY. The blood‐testis barrier: its biology, regulation, and physiological role in spermatogenesis. Curr Top Dev Biol 2005; 71: 263- 96.
• Wu KZ, Li K, Galileo DS, Martin-DeLeon, PA. Juncti- onal adhesion molecule A: Expression in the murine epididymal tract and accessory organs and acquisition by maturing sperm. Mol Human Rep- rod 2017; 23(2): 132-40.
• Wu D, Huang CJ, Jiao XF, Ding ZM, Zhang SX, Miao YL, Huo LJ. Bisphenol AF compromises blood- testis barrier integrity and sperm quality in mi- ce. Chemosphere 2019; 237: 124410.
• Xu J, Anuar F, Mohamed Ali S, Ng MY, Phua DC, Hunziker W. Zona occludens-2 is critical for blood –testis barrier integrity and male fertility. Mol Biol Cell 2009; 20(20): 4268-77.
• Yan HH, Mruk DD, Wong EW, Lee WM, Cheng CY. An autocrine axis in the testis that coordinates spermiation and blood–testis barrier restructuring during spermatogenesis. Proc Natl Acad Sci 2008; 105(26): 8950-5.
• Yan HH, Mruk DD, Lee WM, Cheng CY. Ectoplasmic specialization: A friend or a foe of spermatogene- sis? BioEssays 2007; 29(1): 36-48.
• Yan HH, Cheng CY. Laminin alpha3 forms a complex with beta3 and gamma3 chains that serves as the ligand for alpha6beta1-integrin at the apical ectop- lasmic specialization in adult rat testes. J Biol Chem 2006; 281: 17286-303.
• Ye J, Luo D, Xu X, Sun M, Su X, Tian Z, Zhang M, Yu C, Guan Q. Metformin improves fertility in obe- se males by alleviating oxidative stress-induced blood-testis barrier damage. Oxid Med Cell Lon- gev 2019; 2019: 9151067.
• Yi WEI, Xiang-Liang T, Yu Z, Bin L, Lian-Ju S, Chun- Lan L, Guang-Hui WEI. DEHP exposure destroys blood-testis barrier (BTB) integrity of immature testes through excessive ROS-mediated autop- hagy. Genes Dis 2018; 5(3): 263-74.
• Zhang DC, Chen R, Cai YH, Wang JJ, Yin C, Zou K. Hyperactive reactive oxygen species impair function of porcine Sertoli cells via suppression of surface protein ITGB1 and connexin-43. Zool Res 2020; 41(2): 203.
• Zhou Y, Wang Y. Action and interaction between retinoic acid signaling and blood–testis barrier function in the spermatogenesis cycle. Cells 2022; 11(3): 352.