Document Detail


Regulation of blood-testis barrier dynamics by TGF-beta3 is a Cdc42-dependent protein trafficking event.
MedLine Citation:
PMID:  20534521     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the testis, the blood-testis barrier (BTB) is constituted by specialized junctions between adjacent Sertoli cells in the seminiferous epithelium near the basement membrane. Although the BTB is one of the tightest blood-tissue barriers in the mammalian body, it undergoes extensive restructuring at stage VIII of the seminiferous epithelial cycle to facilitate the transit of preleptotene spermatocytes. Thus, meiosis and postmeiotic germ cell development take place in the seminiferous epithelium behind the BTB. Cytokines (e.g., TGF-beta3) are known to regulate BTB dynamics by enhancing the endocytosis of integral membrane proteins and their intracellular degradation. This thus reduces the levels of proteins above the spermatocytes in transit at the BTB, causing its disruption after testosterone-induced new tight junction (TJ) fibrils are formed behind these cells. By using Sertoli cells cultured in vitro with an established TJ permeability barrier that mimicked the BTB in vivo, Cdc42 was shown to be a crucial regulator that mediated the TGF-beta3-induced BTB disruption. TGF-beta3 was shown to activate Cdc42 to its active GTP-bound form. However, an inactivation of Cdc42 by overexpressing its dominant-negative mutant T17N in Sertoli cell epithelium was shown to block the TGF-beta3-induced acceleration in protein endocytosis. Consequently, this prevented the disruption of Sertoli cell TJ permeability barrier and redistribution of TJ proteins (e.g., CAR and ZO-1) from the cell-cell interface to cell cytosol caused by TGF-beta3. In summary, Cdc42 is a crucial regulatory component in the TGF-beta3-mediated cascade of events that leads to the disruption of the TJ fibrils above the preleptotene spermatocytes to facilitate their transit.
Authors:
Elissa W P Wong; Dolores D Mruk; Will M Lee; C Yan Cheng
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-06-07
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-23     Completed Date:  2010-07-22     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11399-404     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood / metabolism*
Blood-Testis Barrier / metabolism*
Endocytosis
Epithelial Cells / metabolism
Guanosine Triphosphate / metabolism
Male
Rats
Rats, Sprague-Dawley
Seminiferous Epithelium / metabolism
Sertoli Cells / metabolism
Spermatocytes / metabolism
Testis / metabolism*
Tight Junctions / metabolism
Transforming Growth Factor beta3 / metabolism*
cdc42 GTP-Binding Protein / metabolism*
Grant Support
ID/Acronym/Agency:
R01 HD056034/HD/NICHD NIH HHS; R01 HD056034/HD/NICHD NIH HHS; R01 HD056034-02/HD/NICHD NIH HHS; R03 HD061401/HD/NICHD NIH HHS; U54 HD029990/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Transforming Growth Factor beta3; 86-01-1/Guanosine Triphosphate; EC 3.6.5.2/cdc42 GTP-Binding Protein
Comments/Corrections

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