The Experts below are selected from a list of 1833 Experts worldwide ranked by ideXlab platform
C. Yan Cheng - One of the best experts on this subject based on the ideXlab platform.
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Drebrin and Spermatogenesis.
Advances in Experimental Medicine and Biology, 2017Co-Authors: Haiqi Chen, Michelle W. M. Li, C. Yan ChengAbstract:Drebrin is a family of actin-binding proteins with two known members called drebrin A and E. Apart from the ability to stabilize F-actin microfilaments via their actin-binding domains near the N-terminus, drebrin also regulates multiple cellular functions due to its unique ability to recruit multiple binding partners to a specific cellular domain, such as the seminiferous epithelium during the epithelial cycle of spermatogenesis. Recent studies have illustrated the role of drebrin E in the testis during spermatogenesis in particular via its ability to recruit branched actin polymerization protein known as actin-related protein 3 (Arp3), illustrating its involvement in modifying the organization of actin microfilaments at the ectoplasmic specialization (ES) which includes the testis-specific Anchoring Junction at the Sertoli-spermatid (apical ES) interface and at the Sertoli cell-cell (basal ES) interface. These data are carefully evaluated in light of other recent findings herein regarding the role of drebrin in actin filament organization at the ES. We also provide the hypothetical model regarding its involvement in germ cell transport during the epithelial cycle in the seminiferous epithelium to support spermatogenesis.
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Cell polarity proteins and spermatogenesis
Seminars in cell & developmental biology, 2016Co-Authors: Ying Gao, Dolores D. Mruk, Will M. Lee, Wing-yee Lui, Xiang Xiao, C. Yan ChengAbstract:When the cross-section of a seminiferous tubule from an adult rat testes is examined microscopically, Sertoli cells and germ cells in the seminiferous epithelium are notably polarized cells. For instance, Sertoli cell nuclei are found near the basement membrane. On the other hand, tight Junction (TJ), basal ectoplasmic specialization (basal ES, a testis-specific actin-rich Anchoring Junction), gap Junction (GJ) and desmosome that constitute the blood-testis barrier (BTB) are also located near the basement membrane. The BTB, in turn, divides the epithelium into the basal and the adluminal (apical) compartments. Within the epithelium, undifferentiated spermatogonia and preleptotene spermatocytes restrictively reside in the basal compartment whereas spermatocytes and post-meiotic spermatids reside in the adluminal compartment. Furthermore, the heads of elongating/elongated spermatids point toward the basement membrane with their elongating tails toward the tubule lumen. However, the involvement of polarity proteins in this unique cellular organization, in particular the underlying molecular mechanism(s) by which polarity proteins confer cellular polarity in the seminiferous epithelium is virtually unknown until recent years. Herein, we discuss latest findings regarding the role of different polarity protein complexes or modules and how these protein complexes are working in concert to modulate Sertoli cell and spermatid polarity. These findings also illustrate polarity proteins exert their effects through the actin-based cytoskeleton mediated by actin binding and regulatory proteins, which in turn modulate adhesion protein complexes at the cell-cell interface since TJ, basal ES and GJ utilize F-actin for attachment. We also propose a hypothetical model which illustrates the antagonistic effects of these polarity proteins. This in turn provides a unique mechanism to modulate Junction remodeling in the testis to support germ cell transport across the epithelium in particular the BTB during the epithelial cycle of spermatogenesis.
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Coordination of Actin- and Microtubule-Based Cytoskeletons Supports Transport of Spermatids and Residual Bodies/Phagosomes During Spermatogenesis in the Rat Testis.
Endocrinology, 2016Co-Authors: Elizabeth I. Tang, Will M. Lee, C. Yan ChengAbstract:Germ cell transport across the seminiferous epithelium during spermatogenesis requires the intricate coordination of cell Junctions, signaling proteins, and both actin- and microtubule (MT)-based cytoskeletons. Although the involvement of cytoskeletons in germ cell transport has been suggested, the precise mechanism(s) remains elusive. Based on growing evidence that actin and MT interactions underlie fundamental cellular processes, such as cell motility, it is unlikely that actin- and MT-based cytoskeletons work independently to regulate germ cell transport in the testis. Using rats treated with adjudin, a potential male contraceptive that disrupts spermatid adhesion and transport in the testis, as a study model, we show herein that actin- and MT-based cytoskeletons are both necessary for transport of spermatids and residual bodies/phagosomes across the seminiferous epithelium in adult rat testes. Analysis of intratubular expression of F-actin and tubulin revealed disruption of both actin and MT networks, concomitant with misdirected spermatids and phagosomes in rats treated with adjudin. Actin regulatory proteins, epidermal growth factor receptor pathway substrate 8 and actin-related protein 3, were mislocalized and down-regulated at the actin-rich Anchoring Junction between germ and Sertoli cells (apical ectoplasmic specialization) after adjudin treatment. Nonreceptor tyrosine kinase p-FAK-Tyr(407), known to regulate F-actin nucleation via actin-related protein 3, was also mislocalized and down-regulated at the apical ectoplasmic specialization, corroborating the observation of actin cytoskeleton disruption. Additionally, spatiotemporal expression of MT regulatory protein end-binding protein 1, shown to be involved in MT-actin cross talk herein, was also disrupted after adjudin treatment. In summary, spermatid/phagosome transport across the epithelium during spermatogenesis requires the coordination between actin- and MT-based cytoskeletons.
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Plastins regulate ectoplasmic specialization via its actin bundling activity on microfilaments in the rat testis.
Asian journal of andrology, 2016Co-Authors: Chriskc Wong, C. Yan ChengAbstract:Plastins are a family of actin binding proteins (ABPs) known to cross-link actin microfilaments in mammalian cells, creating actin microfilament bundles necessary to confer cell polarity and cell shape. Plastins also support cell movement in response to changes in environment, involved in cell/tissue growth and development. They also confer plasticity to cells and tissues in response to infection or other pathological conditions (e.g., inflammation). In the testis, the cell-cell Anchoring Junction unique to the testis that is found at the Sertoli cell-cell interface at the blood-testis barrier (BTB) and at the Sertoli-spermatid (e.g., 8-19 spermatids in the rat testis) is the basal and the apical ectoplasmic specialization (ES), respectively. The ES is an F-actin-rich Anchoring Junction constituted most notably by actin microfilament bundles. A recent report using RNAi that specifically knocks down plastin 3 has yielded some insightful information regarding the mechanism by which plastin 3 regulates the status of actin microfilament bundles at the ES via its intrinsic actin filament bundling activity. Herein, we provide a brief review on the role of plastins in the testis in light of this report, which together with recent findings in the field, we propose a likely model by which plastins regulate ES function during the epithelial cycle of spermatogenesis via their intrinsic activity on actin microfilament organization in the rat testis.
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Coordination of Actin- and Microtubule-Based Cytoskeletons Supports Transport of Spermatids and Residual Bodies/Phagosomes During Spermatogenesis in the Rat Testis
Endocrinology, 2016Co-Authors: Elizabeth I. Tang, Will M. Lee, C. Yan ChengAbstract:Abstract Germ cell transport across the seminiferous epithelium during spermatogenesis requires the intricate coordination of cell Junctions, signaling proteins, and both actin- and microtubule (MT)-based cytoskeletons. Although the involvement of cytoskeletons in germ cell transport has been suggested, the precise mechanism(s) remains elusive. Based on growing evidencethat actin and MT interactions underlie fundamental cellular processes, such as cell motility, it is unlikely that actin- and MT-based cytoskeletons work independently to regulate germ cell transport in the testis. Using rats treated with adjudin, a potential male contraceptive that disrupts spermatid adhesion and transport in the testis, as a study model, we show herein that actin- and MT-based cytoskeletons are both necessary for transport of spermatids and residual bodies/phagosomes across the seminiferous epithelium in adult rat testes. Analysis of intratubular expression of F-actin and tubulin revealed disruption of both actin and MT networks, concomitant with misdirected spermatids and phagosomes in rats treated with adjudin. Actin regulatory proteins, epidermal growth factor receptor pathway substrate 8 and actin-related protein 3, were mislocalized and down-regulated at the actin-rich Anchoring Junction between germ and Sertoli cells (apical ectoplasmicspecialization) after adjudin treatment. Nonreceptor tyrosine kinase p-FAK-Tyr407, known to regulate F-actin nucleation via actin-related protein 3, was also mislocalized and down-regulated at the apical ectoplasmic specialization, corroborating the observation of actin cytoskeleton disruption. Additionally, spatiotemporal expression of MT regulatory protein end-binding protein 1, shown to be involved in MT-actin cross talk herein, was also disrupted after adjudin treatment. In summary, spermatid/phagosome transport across the epithelium during spermatogenesis requires the coordination between actin- and MT-based cytoskeletons. (Endocrinology 157: 1644–1659, 2016)
Dolores D. Mruk - One of the best experts on this subject based on the ideXlab platform.
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Cell polarity proteins and spermatogenesis
Seminars in cell & developmental biology, 2016Co-Authors: Ying Gao, Dolores D. Mruk, Will M. Lee, Wing-yee Lui, Xiang Xiao, C. Yan ChengAbstract:When the cross-section of a seminiferous tubule from an adult rat testes is examined microscopically, Sertoli cells and germ cells in the seminiferous epithelium are notably polarized cells. For instance, Sertoli cell nuclei are found near the basement membrane. On the other hand, tight Junction (TJ), basal ectoplasmic specialization (basal ES, a testis-specific actin-rich Anchoring Junction), gap Junction (GJ) and desmosome that constitute the blood-testis barrier (BTB) are also located near the basement membrane. The BTB, in turn, divides the epithelium into the basal and the adluminal (apical) compartments. Within the epithelium, undifferentiated spermatogonia and preleptotene spermatocytes restrictively reside in the basal compartment whereas spermatocytes and post-meiotic spermatids reside in the adluminal compartment. Furthermore, the heads of elongating/elongated spermatids point toward the basement membrane with their elongating tails toward the tubule lumen. However, the involvement of polarity proteins in this unique cellular organization, in particular the underlying molecular mechanism(s) by which polarity proteins confer cellular polarity in the seminiferous epithelium is virtually unknown until recent years. Herein, we discuss latest findings regarding the role of different polarity protein complexes or modules and how these protein complexes are working in concert to modulate Sertoli cell and spermatid polarity. These findings also illustrate polarity proteins exert their effects through the actin-based cytoskeleton mediated by actin binding and regulatory proteins, which in turn modulate adhesion protein complexes at the cell-cell interface since TJ, basal ES and GJ utilize F-actin for attachment. We also propose a hypothetical model which illustrates the antagonistic effects of these polarity proteins. This in turn provides a unique mechanism to modulate Junction remodeling in the testis to support germ cell transport across the epithelium in particular the BTB during the epithelial cycle of spermatogenesis.
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New insights into FAK function and regulation during spermatogenesis.
Histology and histopathology, 2014Co-Authors: N Ece Gungor-ordueri, Dolores D. Mruk, Elissa W.p. Wong, Pearl P.y. Lie, Ciler Celik-ozenci, Hin-ting Wan, C. Yan ChengAbstract:Germ cell transport across the seminiferous epithelium during the epithelial cycle is crucial to spermatogenesis, although molecular mechanism(s) that regulate these events remain unknown. Studies have shown that spatiotemporal expression of crucial regulatory proteins during the epithelial cycle represents an efficient and physiologically important mechanism to regulate spermatogenesis without involving de novo synthesis of proteins and/or expression of genes. Herein, we critically review the role of focal adhesion kinase (FAK) in coordinating the transport of spermatids and preleptotene spermatocytes across the epithelium and the BTB, respectively, along the apical ectoplasmic specialization (ES) - blood-testis barrier - basement membrane (BM) functional axis during spermatogenesis. In the testis, p-FAK-Tyr³⁸⁷ and p-FAK-Tyr⁴⁰⁷ are spatiotemporally expressed during the epithelial cycle at the actin-rich Anchoring Junction known as ES, regulating cell adhesion at the Sertoli-spermatid (apical ES) and Sertoli cell-cell (basal ES) interface. Phosphorylated forms of FAK exert their effects by regulating the homeostasis of F-actin at the ES, mediated via their effects on actin polymerization so that microfilaments are efficiently re-organized, such as from their "bundled" to "de-bundled/branched" configuration and vice versa during the epithelial cycle to facilitate the transport of: (i) spermatids across the epithelium, and (ii) preleptotene spermatocytes across the BTB. In summary, p-FAK-Tyr⁴⁰⁷ and p-FAK-Tyr³⁸⁷ are important regulators of spermatogenesis which serve as molecular switches that turn "on" and "off" adhesion function at the apical ES and the basal ES/BTB, mediated via their spatiotemporal expression during the epithelial cycle. A hypothetical model depicting the role of these two molecular switches is also proposed.
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c-Src and c-Yes are Two Unlikely Partners of Spermatogenesis and their Roles in Blood-Testis Barrier Dynamics
Advances in experimental medicine and biology, 2013Co-Authors: Xiang Xiao, Dolores D. Mruk, Faith L. Cheng, C. Yan ChengAbstract:Src family kinases (SFKs), in particular c-Src and c-Yes, are nonreceptor protein tyrosine kinases that mediate integrin signaling at focal adhesion complex at the cell-extracellular matrix interface to regulate cell adhesion, cell cycle progression, cell survival, proliferation and differentiation, most notably in cancer cells during tumorigenesis and metastasis. Interestingly, recent studies have shown that these two proto-oncogenes are integrated components of the stem cell niche and the cell-cell actin-based Anchoring Junction known as ectoplasmic specialization (ES) at the: (1) Sertoli cell-spermatid interface known as apical ES and (2) Sertoli-Sertoli cell interface known as basal ES which together with tight Junctions (TJ), gap Junctions and desmosomes constitute the blood-testis barrier (BTB). At the stem cell niche, these SFKs regulate spermatogonial stem cell (SSC) renewal to maintain the proper population of SSC/spermatogonia for spermatogenesis. At the apical ES and the BTB, c-Src and c-Yes confer cell adhesion either by maintaining the proper phosphorylation status of integral membrane proteins at the site which in turn regulates protein-protein interactions between integral membrane proteins and their adaptors, or by facilitating androgen action on spermatogenesis via a nongenomic pathway which also modulates cell adhesion in the seminiferous epithelium. Herein, we critically evaluate recent findings in the field regarding the roles of these two unlikely partners of spermatogenesis. We also propose a hypothetical model on the mechanistic functions of c-Src and c-Yes in spermatogenesis so that functional experiments can be designed in future studies.
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The apical ectoplasmic specialization-blood-testis barrier functional axis is a novel target for male contraception.
Advances in experimental medicine and biology, 2013Co-Authors: Ka-wai Mok, Dolores D. Mruk, Pearl P.y. Lie, Jayakanthan Mannu, Premendu P. Mathur, Bruno Silvestrini, C. Yan ChengAbstract:The blood-testis barrier (BTB), similar to other blood-tissue barriers, such as the blood-brain barrier and the blood-retinal barrier, is used to protect the corresponding organ from harmful substances (e.g., xenobiotics) including drugs and foreign compounds. More importantly, the BTB allows postmeiotic spermatid development to take place in an immune privileged site at the adluminal (or apical) compartment to avoid the production of antibodies against spermatid-specific antigens, many of which express transiently during spermiogenesis and spermiation. The BTB, however, also poses an obstacle in developing nonhormonal-based male contraceptives by sequestering drugs (e.g., adjudin) that exert their effects on germ cells in the adluminal compartment. The effects of these drugs include disruption of germ cell cycle progression and development, apoptosis, cell adhesion, metabolism and others. Recent studies have demonstrated that there is a functional axis that operates locally in the seminiferous epithelium to co-ordinate different cellular events across the Sertoli cell epithelium, such as spermiation and BTB restructuring during the seminiferous epithelial cycle of spermatogenesis. Components of this functional axis, such as the apical ectoplasmic specialization (apical ES, a testis-specific atypical Anchoring Junction type) and the BTB, in particular their constituent protein complexes, such as a6s1-integrin and occludin at the apical ES and the BTB, respectively, can be the target of male contraception. In this chapter, we highlight recent advances regarding the likely mechanism of action of adjudin in this functional axis with emphasis on the use of molecular modeling technique to facilitate the design of better compounds in male contraceptive development.
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Adjudin, a potential male contraceptive, exerts its effects locally in the seminiferous epithelium of mammalian testes
Reproduction (Cambridge England), 2011Co-Authors: Ka-wai Mok, Dolores D. Mruk, Pearl P.y. Lie, Wing-yee Lui, C. Y. ChengAbstract:Adjudin is a derivative of 1H-indazole-3-carboxylic acid that was shown to have potent anti-spermatogenic activity in rats rabbits and dogs. It exerts its effects most notably locally in the apical compartment of the seminiferous epithelium behind the blood-testis barrier (BTB) by disrupting adhesion of spermatids to the Sertoli cells thereby inducing release of immature spermatids from the epithelium that leads to infertility. After adjudin is metabolized the remaining spermatogonial stem cells (SSC) and spermatogonia repopulate the seminiferous epithelium gradually via spermatogonial self-renewal and differentiation to be followed by meiosis and spermiogenesis and thus fertility rebounds. Recent studies in rats have demonstrated unequivocally that the primary cellular target of adjudin in the testis is the apical ectoplasmic specialization (apical ES) a testis-specific Anchoring Junction type restricted to the interface between Sertoli cells and elongating spermatids (from step 8-19 spermatids). In this brief review we highlight some of the recent advances and obstacles regarding the possible use of adjudin as a male contraceptive.
Will M. Lee - One of the best experts on this subject based on the ideXlab platform.
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Cell polarity proteins and spermatogenesis
Seminars in cell & developmental biology, 2016Co-Authors: Ying Gao, Dolores D. Mruk, Will M. Lee, Wing-yee Lui, Xiang Xiao, C. Yan ChengAbstract:When the cross-section of a seminiferous tubule from an adult rat testes is examined microscopically, Sertoli cells and germ cells in the seminiferous epithelium are notably polarized cells. For instance, Sertoli cell nuclei are found near the basement membrane. On the other hand, tight Junction (TJ), basal ectoplasmic specialization (basal ES, a testis-specific actin-rich Anchoring Junction), gap Junction (GJ) and desmosome that constitute the blood-testis barrier (BTB) are also located near the basement membrane. The BTB, in turn, divides the epithelium into the basal and the adluminal (apical) compartments. Within the epithelium, undifferentiated spermatogonia and preleptotene spermatocytes restrictively reside in the basal compartment whereas spermatocytes and post-meiotic spermatids reside in the adluminal compartment. Furthermore, the heads of elongating/elongated spermatids point toward the basement membrane with their elongating tails toward the tubule lumen. However, the involvement of polarity proteins in this unique cellular organization, in particular the underlying molecular mechanism(s) by which polarity proteins confer cellular polarity in the seminiferous epithelium is virtually unknown until recent years. Herein, we discuss latest findings regarding the role of different polarity protein complexes or modules and how these protein complexes are working in concert to modulate Sertoli cell and spermatid polarity. These findings also illustrate polarity proteins exert their effects through the actin-based cytoskeleton mediated by actin binding and regulatory proteins, which in turn modulate adhesion protein complexes at the cell-cell interface since TJ, basal ES and GJ utilize F-actin for attachment. We also propose a hypothetical model which illustrates the antagonistic effects of these polarity proteins. This in turn provides a unique mechanism to modulate Junction remodeling in the testis to support germ cell transport across the epithelium in particular the BTB during the epithelial cycle of spermatogenesis.
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Coordination of Actin- and Microtubule-Based Cytoskeletons Supports Transport of Spermatids and Residual Bodies/Phagosomes During Spermatogenesis in the Rat Testis.
Endocrinology, 2016Co-Authors: Elizabeth I. Tang, Will M. Lee, C. Yan ChengAbstract:Germ cell transport across the seminiferous epithelium during spermatogenesis requires the intricate coordination of cell Junctions, signaling proteins, and both actin- and microtubule (MT)-based cytoskeletons. Although the involvement of cytoskeletons in germ cell transport has been suggested, the precise mechanism(s) remains elusive. Based on growing evidence that actin and MT interactions underlie fundamental cellular processes, such as cell motility, it is unlikely that actin- and MT-based cytoskeletons work independently to regulate germ cell transport in the testis. Using rats treated with adjudin, a potential male contraceptive that disrupts spermatid adhesion and transport in the testis, as a study model, we show herein that actin- and MT-based cytoskeletons are both necessary for transport of spermatids and residual bodies/phagosomes across the seminiferous epithelium in adult rat testes. Analysis of intratubular expression of F-actin and tubulin revealed disruption of both actin and MT networks, concomitant with misdirected spermatids and phagosomes in rats treated with adjudin. Actin regulatory proteins, epidermal growth factor receptor pathway substrate 8 and actin-related protein 3, were mislocalized and down-regulated at the actin-rich Anchoring Junction between germ and Sertoli cells (apical ectoplasmic specialization) after adjudin treatment. Nonreceptor tyrosine kinase p-FAK-Tyr(407), known to regulate F-actin nucleation via actin-related protein 3, was also mislocalized and down-regulated at the apical ectoplasmic specialization, corroborating the observation of actin cytoskeleton disruption. Additionally, spatiotemporal expression of MT regulatory protein end-binding protein 1, shown to be involved in MT-actin cross talk herein, was also disrupted after adjudin treatment. In summary, spermatid/phagosome transport across the epithelium during spermatogenesis requires the coordination between actin- and MT-based cytoskeletons.
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Coordination of Actin- and Microtubule-Based Cytoskeletons Supports Transport of Spermatids and Residual Bodies/Phagosomes During Spermatogenesis in the Rat Testis
Endocrinology, 2016Co-Authors: Elizabeth I. Tang, Will M. Lee, C. Yan ChengAbstract:Abstract Germ cell transport across the seminiferous epithelium during spermatogenesis requires the intricate coordination of cell Junctions, signaling proteins, and both actin- and microtubule (MT)-based cytoskeletons. Although the involvement of cytoskeletons in germ cell transport has been suggested, the precise mechanism(s) remains elusive. Based on growing evidencethat actin and MT interactions underlie fundamental cellular processes, such as cell motility, it is unlikely that actin- and MT-based cytoskeletons work independently to regulate germ cell transport in the testis. Using rats treated with adjudin, a potential male contraceptive that disrupts spermatid adhesion and transport in the testis, as a study model, we show herein that actin- and MT-based cytoskeletons are both necessary for transport of spermatids and residual bodies/phagosomes across the seminiferous epithelium in adult rat testes. Analysis of intratubular expression of F-actin and tubulin revealed disruption of both actin and MT networks, concomitant with misdirected spermatids and phagosomes in rats treated with adjudin. Actin regulatory proteins, epidermal growth factor receptor pathway substrate 8 and actin-related protein 3, were mislocalized and down-regulated at the actin-rich Anchoring Junction between germ and Sertoli cells (apical ectoplasmicspecialization) after adjudin treatment. Nonreceptor tyrosine kinase p-FAK-Tyr407, known to regulate F-actin nucleation via actin-related protein 3, was also mislocalized and down-regulated at the apical ectoplasmic specialization, corroborating the observation of actin cytoskeleton disruption. Additionally, spatiotemporal expression of MT regulatory protein end-binding protein 1, shown to be involved in MT-actin cross talk herein, was also disrupted after adjudin treatment. In summary, spermatid/phagosome transport across the epithelium during spermatogenesis requires the coordination between actin- and MT-based cytoskeletons. (Endocrinology 157: 1644–1659, 2016)
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Connexin 43 and plakophilin-2 as a protein complex that regulates blood–testis barrier dynamics
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Dolores D. Mruk, Will M. Lee, C. Yan ChengAbstract:The blood–testis barrier (BTB) formed by adjacent Sertoli cells is composed of coexisting tight Junction (TJ), basal ectoplasmic specialization (ES), and desmosome-like Junction. Desmosome-like Junctions display structural features of desmosome and gap Junctions, but its function at the BTB remains unknown. Herein, we demonstrate that connexin 43 (Cx43), a gap Junction integral membrane protein, structurally interacts with desmosomal protein plakophilin-2 (PKP2), basal ES proteins N-cadherin and β-catenin, and signaling molecule c-Src, but not with the TJ proteins occludin and ZO-1 in the seminiferous epithelium of adult rats. The localization of Cx43 in the seminiferous epithelium during (i) the normal epithelial cycle of spermatogenesis and (ii) Anchoring Junction restructuring at the Sertoli–spermatid interface induced by adjudin which mimics Junction restructuring events during spermatogenesis have suggested that Cx43 is involved in cell adhesion. The knockdown of Cx43 by RNAi technique using specific siRNA duplexes was performed in primary Sertoli cell cultures with an established TJ permeability barrier that mimicked the BTB in vivo. This knockdown of Cx43 affected neither the TJ barrier function nor the steady-state levels of Junction proteins of TJ, basal ES, and desmosome-like Junction. However, after the knockdown of both Cx43 and PKP2, the Sertoli cell TJ barrier function was perturbed transiently. This perturbation was concomitant with a mislocalization of occludin and ZO-1 from the cell–cell interface. In summary, Cx43 and PKP2 form a protein complex within the desmosome-like Junction to regulate cell adhesion at the BTB, partly through its effects on the occludin/ZO-1 complex, so as to facilitate the transit of primary preleptotene spermatocytes.
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Epidermal growth factor receptor pathway substrate 8 (Eps8) is a novel regulator of cell adhesion and the blood‐testis barrier integrity in the seminiferous epithelium
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2009Co-Authors: Pearl P.y. Lie, Dolores D. Mruk, Will M. Lee, C. Yan ChengAbstract:In the seminiferous epithelium, Eps8 is localized to actin-based cell Junctions at the blood-testis barrier (BTB) and the apical ectoplasmic specialization (ES) in stage V–VI tubules but is considerably diminished in stage VIII tubules. Eps8 down-regulation coincides with the time of BTB restructuring and apical ES disassembly, implicating the role of Eps8 in cell adhesion. Its involvement in Sertoli-germ cell adhesion was substantiated in studies using an in vivo animal model by treating rats with 1-(2,4-dichlorobenzy)-1H-indazole-3-carbohydrazide (adjudin) to induce Anchoring Junction restructuring, during which Eps8 disappeared at the apical ES before germ cell departure. In Sertoli cell cultures with established permeability barrier mimicking the BTB in vivo, the knockdown of Eps8 by RNAi led to F-actin disorganization and the mislocalization of the tight Junction proteins occludin and ZO-1, suggesting the function of Eps8 in maintaining BTB integrity. In vivo knockdown of Eps8 in the testis caused ge...
Masanobu Satoh - One of the best experts on this subject based on the ideXlab platform.
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Retinoic acid disintegrated desmosomes and hemidesmosomes in stratified oral keratinocytes.
Journal of Oral Pathology & Medicine, 2004Co-Authors: Setsuko Hatakeyama, A. Otsubo, Yuko Oikawa, Katsuhiko Yoshimoto, Y Yoshida, S. Hayashi, Masanobu SatohAbstract:Background: Although it is known that retinoic acid (RA) regulates the cellular differentiation of skin keratinocytes, the effects of RA on the Anchoring Junction have not been clarified. The effects of all-trans RA on cell–cell and cell–matrix connections of gingival epithelial (GE)1 cells in a multilayered culture were investigated. Methods: Ultrastructures of GE1 cells were observed and immunohistochemistry was used to detect keratin 4, keratin 13, and desmoglein expression. Reverse transcription-polymerase chain reaction was performed to detect expression of desmosome and hemidesmosome-associating adhesion molecules, keratin 13, and keratin14. Results: Retinoic acid caused immunohistochemical diminution of keratin 4, keratin 13, and desmoglein. Ultrastructurally, RA induced drastic loss of typical desmosomes and complete loss of hemidesmosomes. RA significantly decreased the transcript levels of keratin 13, keratin 14, desmoglein 1, and desmocollin 1 in a dose-dependent manner. The 230-kD bullous pemphigoid antigen (BPAG1) gene expression was also reduced by RA, whereas transcript levels of integrin α6, integrin β4, the 180-kD bullous pemphigoid antigen (BPAG2), and laminin 5 were not affected. Conclusion: These results indicated that RA disintegrated not only desmosomes by depriving the cells of desmoglein 1, desmocollin 1, keratin 13, and keratin 4, but also hemidesmosomes by reducing the expression of BPAG1 and keratin 14 in basal keratinocytes.
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Retinoic acid disintegrated desmosomes and hemidesmosomes in stratified oral keratinocytes.
Journal of Oral Pathology & Medicine, 2004Co-Authors: Setsuko Hatakeyama, A. Otsubo, Yuko Oikawa, Katsuhiko Yoshimoto, Y Yoshida, S. Hayashi, Masanobu SatohAbstract:Background: Although it is known that retinoic acid (RA) regulates the cellular differentiation of skin keratinocytes, the effects of RA on the Anchoring Junction have not been clarified. The effects of all-trans RA on cell–cell and cell–matrix connections of gingival epithelial (GE)1 cells in a multilayered culture were investigated. Methods: Ultrastructures of GE1 cells were observed and immunohistochemistry was used to detect keratin 4, keratin 13, and desmoglein expression. Reverse transcription-polymerase chain reaction was performed to detect expression of desmosome and hemidesmosome-associating adhesion molecules, keratin 13, and keratin14. Results: Retinoic acid caused immunohistochemical diminution of keratin 4, keratin 13, and desmoglein. Ultrastructurally, RA induced drastic loss of typical desmosomes and complete loss of hemidesmosomes. RA significantly decreased the transcript levels of keratin 13, keratin 14, desmoglein 1, and desmocollin 1 in a dose-dependent manner. The 230-kD bullous pemphigoid antigen (BPAG1) gene expression was also reduced by RA, whereas transcript levels of integrin α6, integrin β4, the 180-kD bullous pemphigoid antigen (BPAG2), and laminin 5 were not affected. Conclusion: These results indicated that RA disintegrated not only desmosomes by depriving the cells of desmoglein 1, desmocollin 1, keratin 13, and keratin 4, but also hemidesmosomes by reducing the expression of BPAG1 and keratin 14 in basal keratinocytes.
Weiliang Xia - One of the best experts on this subject based on the ideXlab platform.
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Adjudin--A Male Contraceptive with Other Biological Activities.
Recent patents on endocrine metabolic & immune drug discovery, 2015Co-Authors: Yan-ho Cheng, Weiliang Xia, Elissa W.p. Wong, Qian R. Xie, Jiaxiang Shao, Tengyuan Liu, Yizhou Quan, Tingting Zhang, Xiao Yang, Keyi GengAbstract:BACKGROUND: Adjudin has been explored as a male contraceptive for the last 15 years since its initial synthesis in the late 1990s. More than 50 papers have been published and listed in PubMed in which its mechanism that induces exfoliation of germ cells from the seminiferous epithelium such as its effects on actin microfilaments at the apical ES (ectoplasmic specialization a testis-specific actin-rich Anchoring Junction) has been delineated. OBJECTIVE: Recent studies have demonstrated that besides its activity to induce germ cell exfoliation from the seminiferous epithelium to cause reversible infertility in male rodents adjudin possesses other biological activities which include anti-cancer anti-inflammation in the brain and anti-ototoxicity induced by gentamicin in rodents. Results of these findings likely spark the interest of investigators to explore other medical use of this and other indazole-based compounds possibly mediated by the signaling pathway(s) in the mitochondria of mammalian cells following treatment with adjudin. In this review we carefully evaluate these recent findings. METHODS: Papers published and listed at www.pubmed.org and patents pertinent to adjudin and its related compounds were searched. Findings were reviewed and critically evaluated and reviewed and summarized herein. RESULTS: Adjudin is a novel compound that possesses the anti-spermatogenetic activity. Furthermore it possesses anti-cancer anti-inflammation anti-neurodegeneration and anti-ototoxicity activities based on studies using different in vitro and in vivo models. CONCLUSION: Studies on adjudin should be expanded to better understand its biological activities so that it can become a useful drug for treatment of other ailments besides serving as a male contraceptive.
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TGF-β3 regulates Anchoring Junction dynamics in the seminiferous epithelium of the rat testis via the Ras/ERK signaling pathway : An in vivo study
Developmental biology, 2005Co-Authors: Weiliang Xia, C. Yan ChengAbstract:Abstract Recent studies have shown that transforming growth factor (TGF)-β3 regulates blood–testis barrier (BTB) dynamics in vivo, plausibly by determining the steady-state levels of occludin and zonula occludens-1 (ZO-1) at the BTB site via the p38 MAP kinase signaling pathway. Since BTB is composed of coexisting TJs and basal ectoplasmic specializations [ES, a testis-specific adherens Junction (AJ) type] in the seminiferous epithelium of the rat testis, we sought to examine if TGF-β3 would also regulate Anchoring Junction dynamics. Using an in vivo model in which rats were treated with AF-2364 [1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide] to perturb Sertoli–germ cell AJs without affecting the integrity of TJs at the BTB, it was noted that the event of germ cell loss from the epithelium was associated with a transient surge in TGF-β3. Furthermore, it was also associated with a surge in the protein levels of Ras, p-ERK, and the intrinsic activity of ERK, illustrating TGF-β3 apparently regulates Sertoli–germ cell ES function via the Ras/MEK/ERK signaling pathway. Indeed, pretreatment of rats with TβRII/Fc chimera, a TGF-β antagonist, or U0126, a specific MEK inhibitor, could significantly delay and partially block the disruptive effects of AF-2364 in depleting germ cells from the epithelium. While the protein levels of the cadherin/catenin complex were significantly induced during AF-2364-mediated germ cell loss, perhaps being used to retain germ cells in the epithelium, this increase failed to reverse the loss of adhesion function between Sertoli and germ cells because of a loss of protein–protein interactions between cadherins and catenins. Collectively, these results illustrate that the testis has a novel mechanism in place in which an agent that primarily disrupts TJs can induce secondary loss of AJ function, leading to germ cell loss from the seminiferous epithelium. Yet an agent that selectively disrupts AJs (e.g., AF-2364) can limit its effects exclusively at the Sertoli–germ cell adhesive site without perturbing the Sertoli–Sertoli TJs.
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tgf β3 regulates Anchoring Junction dynamics in the seminiferous epithelium of the rat testis via the ras erk signaling pathway an in vivo study
Developmental Biology, 2005Co-Authors: Weiliang Xia, Yan C ChengAbstract:Abstract Recent studies have shown that transforming growth factor (TGF)-β3 regulates blood–testis barrier (BTB) dynamics in vivo, plausibly by determining the steady-state levels of occludin and zonula occludens-1 (ZO-1) at the BTB site via the p38 MAP kinase signaling pathway. Since BTB is composed of coexisting TJs and basal ectoplasmic specializations [ES, a testis-specific adherens Junction (AJ) type] in the seminiferous epithelium of the rat testis, we sought to examine if TGF-β3 would also regulate Anchoring Junction dynamics. Using an in vivo model in which rats were treated with AF-2364 [1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide] to perturb Sertoli–germ cell AJs without affecting the integrity of TJs at the BTB, it was noted that the event of germ cell loss from the epithelium was associated with a transient surge in TGF-β3. Furthermore, it was also associated with a surge in the protein levels of Ras, p-ERK, and the intrinsic activity of ERK, illustrating TGF-β3 apparently regulates Sertoli–germ cell ES function via the Ras/MEK/ERK signaling pathway. Indeed, pretreatment of rats with TβRII/Fc chimera, a TGF-β antagonist, or U0126, a specific MEK inhibitor, could significantly delay and partially block the disruptive effects of AF-2364 in depleting germ cells from the epithelium. While the protein levels of the cadherin/catenin complex were significantly induced during AF-2364-mediated germ cell loss, perhaps being used to retain germ cells in the epithelium, this increase failed to reverse the loss of adhesion function between Sertoli and germ cells because of a loss of protein–protein interactions between cadherins and catenins. Collectively, these results illustrate that the testis has a novel mechanism in place in which an agent that primarily disrupts TJs can induce secondary loss of AJ function, leading to germ cell loss from the seminiferous epithelium. Yet an agent that selectively disrupts AJs (e.g., AF-2364) can limit its effects exclusively at the Sertoli–germ cell adhesive site without perturbing the Sertoli–Sertoli TJs.
