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Chen H.,The Mary M Wohlford Laboratory For Male Contraceptive Research | Cheng C.Y.,The Mary M Wohlford Laboratory For Male Contraceptive Research
Seminars in Cell and Developmental Biology

In adult mammalian testes, spermatogenesis is comprised of several discrete cellular events that work in tandem to support the transformation and differentiation of diploid spermatogonia to haploid spermatids in the seminiferous epithelium during the seminiferous epithelial cycle. These include: self-renewal of spermatogonial stem cells via mitosis and their transformation into differentiated spermatogonia, meiosis I/II, spermiogenesis and the release of sperms at spermiation. Studies have shown that these cellular events are under precise and coordinated controls of multiple proteins and signaling pathways. These events are also regulated by polarity proteins that are known to confer classical apico-basal (A/B) polarity in other epithelia. Furthermore, spermatid development is likely supported by planar cell polarity (PCP) proteins since polarized spermatids are aligned across the plane of seminiferous epithelium in an orderly fashion, analogous to hair cells in the cochlea of the inner ear. Thus, the maximal number of spermatids can be packed and supported by a fixed population of differentiated Sertoli cells in the limited space of the seminiferous epithelium in adult testes. In this review, we briefly summarize recent findings regarding the role of PCP proteins in the testis. This information should be helpful in future studies to better understand the role of PCP proteins in spermatogenesis. © 2016 Elsevier Ltd. Source

Li N.,The Mary M Wohlford Laboratory For Male Contraceptive Research | Yan Cheng C.,The Mary M Wohlford Laboratory For Male Contraceptive Research
Histology and Histopathology

mTOR (mammalian target of rapamycin) is one of the most important signaling molecules in mammalian cells which regulates an array of cellular events, ranging from cell metabolism to cell proliferation. Based on the association of mTOR with the core component proteins, such as Raptor (regulatoryassociated protein of mTOR) or Rictor (rapamycinintensive companion of mTOR), mTOR can become the mTORC1 (mammalian target of rapamycin complex 1) or mTORC2, respectively. Studies have shown that during the epithelial cycle of spermatogenesis, mTORC1 promotes remodeling and restructuring of the bloodtestis barrier (BTB) in vitro and in vivo, making the Sertoli cell tight junction (TJ)-permeability barrier “leaky”; whereas mTORC2 promotes BTB integrity, making the Sertoli cell TJ-barrier “tighter”. These contrasting effects, coupled with the spatiotemporal expression of the core signaling proteins at the BTB that confer the respective functions of mTORC1 vs. mTORC2 thus provide a unique mechanism to modulate BTB dynamics, allowing or disallowing the transport of biomolecules and also preleptotene spermatocytes across the immunological barrier. More importantly, studies have shown that these changes to BTB dynamics conferred by mTORC1 and mTORC2 are mediated by changes in the organization of the actin microfilament networks at the BTB, and involve gap junction (GJ) intercellular communication. Since GJ has recently been shown to be crucial to reboot spermatogenesis and meiosis following toxicant-induced aspermatogenesis, these findings thus provide new insightful information regarding the integration of mTOR and GJ to regulate spermatogenesis. © 2016, Histology and Histopathology. All rights reserved. Source

Gungor-Ordueri N.E.,The Mary M Wohlford Laboratory For Male Contraceptive Research | Celik-Ozenci C.,Akdeniz University | Cheng C.Y.,The Mary M Wohlford Laboratory For Male Contraceptive Research
American Journal of Physiology - Endocrinology and Metabolism

In the testis, spermatids are polarized cells, with their heads pointing toward the basement membrane during maturation. This polarity is crucial to pack the maximal number of spermatids in the seminiferous epithelium so that millions of sperms can be produced daily. A loss of spermatid polarity is detected after rodents are exposed to toxicants (e.g., cadmium) or nonhormonal male contraceptives (e.g., adjudin), which is associated with a disruption on the expression and/or localization of polarity proteins. In the rat testis, fascin 1, an actin-bundling protein found in mammalian cells, was expressed by Sertoli and germ cells. Fascin 1 was a component of the ectoplasmic specialization (ES), a testis-specific anchoring junction known to confer spermatid adhesion and polarity. Its expression in the seminiferous epithelium was stage specific. Fascin 1 was localized to the basal ES at the Sertoli cell-cell interface of the blood-testis barrier in all stages of the epithelial cycle, except it diminished considerably at late stage VIII. Fascin 1 was highly expressed at the apical ES at stage VII–early stage VIII and restricted to the step 19 spermatids. Its knockdown by RNAi that silenced fascin 1 by ∼70% in Sertoli cells cultured in vitro was found to perturb the tight junction-permeability barrier via a disruption of F-actin organization. Knockdown of fascin 1 in vivo by ∼60–70% induced defects in spermatid polarity, which was mediated by a mislocalization and/or downregulation of actin-bundling proteins Eps8 and palladin, thereby impeding F-actin organization and disrupting spermatid polarity. In summary, these findings provide insightful information on spermatid polarity regulation. © 2014 the American Physiological Society. Source

Li M.W.,The Mary M Wohlford Laboratory For Male Contraceptive Research
Advances in experimental medicine and biology

Gap junction is a cell-cell communication junction type found in virtually all mammalian epithelia and endothelia and provides the necessary "signals" to coordinate physiological events to maintain the homeostasis of an epithelium and/or endothelium under normal physiological condition and following changes in the cellular environment (e.g., stimuli from stress, growth, development, inflammation, infection). Recent studies have illustrated the significance of this junction type in the maintenance of different blood-tissue barriers, most notably the blood-brain barrier and blood-testis barrier, which are dynamic ultrastructures, undergoing restructuring in response to stimuli from the environment. In this chapter, we highlight and summarize the latest findings in the field regarding how changes at the gap junction, such as the result of a knock-out, knock-down, knock-in, or gap junction inhibition and/or its activation via the use of inhibitors and/or activators, would affect the integrity or permeability of the blood-tissue barriers. These findings illustrate that much research is needed to delineate the role of gap junction in the blood-tissue barriers, most notably its likely physiological role in mediating or regulating the transport of therapeutic drugs across the blood-tissue barriers. Source

Tang E.I.,The Mary M Wohlford Laboratory For Male Contraceptive Research | Mruk D.D.,The Mary M Wohlford Laboratory For Male Contraceptive Research | Cheng C.Y.,The Mary M Wohlford Laboratory For Male Contraceptive Research
Seminars in Cell and Developmental Biology

In rodents and humans, testicular cells, similar to other mammalian cells, are supported by actin-, microtubule (MT)- and intermediate filament-based cytoskeletons. Although the cytoskeletal network of the testis serves an important role in regulating spermatogenesis during the epithelial cycle, most of the published findings in the literature are limited to studies that only visualize these cytoskeletons in the seminiferous epithelium. Few focus on the underlying molecular mechanism that regulates their organization in the epithelium in response to changes in the stages of the epithelial cycle. Functional studies in the last decade have begun to focus on the role of binding proteins that regulate these cytoskeletons, with some interesting findings rapidly emerging in the field. Since the actin- and intermediate-based cytoskeletons have been recently reviewed, herein we focus on the MT-based cytoskeleton for two reasons. First, besides serving as a structural support cytoskeleton, MTs are known to serve as the track to support and facilitate the transport of germ cells, such as preleptotene spermatocytes connected in clones and elongating/elongated spermatids during spermiogenesis, across the blood-testis barrier (BTB) and the adluminal compartment, respectively, during spermatogenesis. While these cellular events are crucial to the completion of spermatogenesis, they have been largely ignored in the past. Second, MT-based cytoskeleton is working in concert with the actin-based cytoskeleton to provide structural support for the transport of intracellular organelles across the cell cytosol, such as endosome-based vesicles, and phagosomes, which contain residual bodies detached from spermatids, to maintain the cellular homeostasis in the seminiferous epithelium. We critically evaluate some recent published findings herein to support a hypothesis regarding the role of MT in conferring germ cell transport in the seminiferous epithelium. © 2016 Elsevier Ltd. Source

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