Proliferation of Adult Sertoli Cells Following Conditional Knockout of the Gap Junctional Protein GJA1 (Connexin 43) in Mice1

Sridharan, Santhi; Simon, Liz; Meling, Daryl D.; Cyr, Daniel G.; Gutstein, David E.; Fishman, Glenn I.; Guillou, Florian; Cooke, Paul S.

doi:10.1095/biolreprod.106.059212

Cited by 206 publications

(213 citation statements)

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“…These findings are also supported by the phenotypes observed in mice and humans with lower levels of Cx43. Adult Sertoli cellspecific Cx43 knockout (SC-Cx43 KO) mice displayed spermatogenic arrest at the spermatogonial level (18,19). Sertoli cells were found to undergo mitotic proliferation without differentiation and sloughing of Sertoli cell clusters can be found at the lumen of the seminiferous tubule (18).…”

Section: Discussionmentioning

confidence: 99%

Connexin 43 is critical to maintain the homeostasis of the blood–testis barrier via its effects on tight junction reassembly

Mruk²,

Lee³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

146

122

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In mammalian testes, the blood-testis barrier (BTB) or Sertoli cell barrier created by specialized junctions between Sertoli cells near the basement membrane confers an immunological barrier by sequestering the events of meiotic division and postmeiotic germ cell development from the systemic circulation. The BTB is constituted by coexisting tight junctions (TJs), basal ectoplasmic specializations, desmosomes, and gap junctions. Despite being one of the tightest blood-tissue barriers, the BTB has to restructure cyclically during spermatogenesis. A recent study showed that gap junction protein connexin 43 (Cx43) and desmosome protein plakophilin-2 are working synergistically to modulate the BTB integrity by regulating the distribution of TJ-associated proteins at the Sertoli-Sertoli cell interface. However, the precise role of Cx43 in regulating the cyclical restructuring of junctions remains obscure. In this report, the calcium switch and the bisphenol A (BPA) models were used to induce junction restructuring in primary cultures of Sertoli cells isolated from rat testes that formed a TJ-permeability barrier that mimicked the BTB in vivo. The removal of calcium by EGTA perturbed the Sertoli cell tight junction barrier, but calcium repletion allowed the "resealing" of the disrupted barrier. However, a knockdown of Cx43 in Sertoli cells by RNAi significantly reduced the kinetics of TJ-barrier resealing. These observations were confirmed using the bisphenol A model in which the knockdown of Cx43 by RNAi also perturbed the TJ-barrier reassembly following BPA removal. In summary, Cx43 is crucial for TJ reassembly at the BTB during its cyclic restructuring throughout the seminiferous epithelial cycle of spermatogenesis.bisphenol A | calcium switch | gap junction | seminiferous epithelial cycle | spermatogenesis I n mammalian testes, the blood-testis barrier (BTB) segregates the epithelium of seminiferous tubules into apical and basal compartments (1, 2). Unlike other blood-tissue barriers (e.g., blood-brain barrier, blood-retina barrier) that are constituted by tight junctions (TJs) between endothelial cells of the microvessels at the apical region, the BTB is created by adjacent Sertoli cells in the seminiferous epithelium near the basement membrane. The BTB is constituted by coexisting TJs, basal ectoplasmic specialization (basal ES, a testis-specific adherens junction type), desmosome-like junction (or desmosome-gap junction), and gap junction (GJ) (1-3). Whereas the BTB is one of the tightest blood-tissue barriers, it undergoes cyclical restructuring to accommodate the transit of preleptotene spermatocytes from the basal to the apical compartment during spermatogenesis, so that meiotic divisions and postmeiotic germ cell development (i.e., spermiogenesis) can take place in the apical compartment of the seminiferous epithelium behind this immunological barrier. The immunological barrier conferred by the BTB cannot be compromised, even transiently, during the transit of preleptotene spermatocytes to avoid the product...

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Section: Discussionmentioning

confidence: 99%

Connexin 43 is critical to maintain the homeostasis of the blood–testis barrier via its effects on tight junction reassembly

Mruk²,

Lee³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

146

122

View full text Add to dashboard Cite

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“…Furthermore, it has been verified in numerous publications that the lack of even a single junctional protein localised at the BTB results in distinct testicular phenotypes and mostly causes sterility; see also Table 1 for more details (Reaume et al 1995, Gow et al 1999, Juneja et al 1999, Saitou et al 2000, Brehm et al 2007, Sridharan et al 2007, Weider et al 2011a,b, Chojnacka et al 2012, Giese et al 2012, Gerber et al 2014, Jiang et al 2014, 2015, Gerber 2015, Noelke et al 2015. It may also be mentionable in this context that it was reported in different studies that BTB components may act as early targets of environmental and reproductive toxicants mostly leading to testicular disorders (Defamie et al 2001, Sobarzo et al 2006, 2009, Li et al 2009a, Salian et al 2009, Pointis et al 2011.…”

Section: Sc Btb and Junctional Proteinsmentioning

confidence: 96%

“…This process is believed to coincide with the termination of SC proliferation and their functional maturation. The direct cell-cell interactions within the seminiferous tubules are mainly dependent upon tight, adherens, and gap junctions as these different junction types have been identified and located between SC (Cyr et al 1999, Mruk & Cheng 2004, Brehm et al 2007, Sridharan et al 2007, Weider et al 2011a, Gerber et al 2014, Gerber 2015, Noelke et al 2015.…”

Section: Sc Btb and Junctional Proteinsmentioning

confidence: 99%

“…The most predominant gap junction protein within the testis of different species so far is CX43 (e.g. Steger et al 1999, St-Pierre et al 2003, Brehm & Steger 2005, Bergmann 2006, Brehm et al 2006, Sridharan et al 2007, Weider et al 2011a, Almeida et al 2012, Gerber et al 2014, Gerber 2015, Noelke et al 2015, Rode et al 2015. As found in most animal cell types, gap junction channels allow for direct cytoplasmic connection between adjacent cells.…”

Section: R17mentioning

confidence: 99%

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Blood–testis barrier and Sertoli cell function: lessons from SCCx43KO mice

Gerber¹,

Heinrich²,

Brehm³

2016

Reproduction

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The gap junction protein connexin43 (CX43) plays a vital role in mammalian spermatogenesis by allowing for direct cytoplasmic communication between neighbouring testicular cells. In addition, different publications suggest that CX43 in Sertoli cells (SC) might be important for blood-testis barrier (BTB) formation and BTB homeostasis. Thus, through the use of the Cre-LoxP recombination system, a transgenic mouse line was developed in which only SC are deficient of the gap junction protein, alpha 1 (Gja1) gene. Gja1 codes for the protein CX43. This transgenic mouse line has been commonly defined as the SC specific CX43 knockout (SCCx43KO) mouse line. Within the seminiferous tubule, SC aid in spermatogenesis by nurturing germ cells and help them to proliferate and mature. Owing to the absence of CX43 within the SC, homozygous KO mice are infertile, have reduced testis size, and mainly exhibit spermatogenesis arrest at the level of spermatogonia, seminiferous tubules containing only SC (SC-only syndrome) and intratubular SC-clusters. Although the SC specific KO of CX43 does not seem to have an adverse effect on BTB integrity, CX43 influences BTB composition as the expression pattern of different BTB proteins (like OCCLUDIN, b-CATENIN, N-CADHERIN, and CLAUDIN11) is altered in mutant males. The supposed roles of CX43 in dynamic BTB regulation, BTB assembly and/or disassembly and its possible interaction with other junctional proteins composing this unique barrier are discussed. Data collectively indicate that CX43 might represent an important regulator of dynamic BTB formation, composition and function.Reproduction (2016) 151 R15-R27

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“…L'approche ex vivo a permis de montrer que la Cx43 localisée entre les cellules de Sertoli et les spermatogonies est impliquée dans la survie de ces cellules germinales et que la Cx43 des jonctions entre cellules de Sertoli participe au contrôle de la prolifé-ration de ces dernières [18]. De même, les modèles de knock-out (KO) conditionnel pour le gène Cx43, montrent que la Cx43 est essentielle au contrôle de la prolifération et de la différenciation des cellules de Sertoli [19]. Dans ces cocultures, Vigier et al ont montré que la FSH et la testostérone, à des concentrations physiologiques, ont des effets positifs et redondants sur les deux divisions de la méiose et sur l'expression de gènes exprimés par les cellules germinales haploïdes [20].…”

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