Document Detail

Sertoli-germ cell adherens junction dynamics in the testis are regulated by RhoB GTPase via the ROCK/LIMK signaling pathway.
MedLine Citation:
PMID:  12606349     Owner:  NLM     Status:  MEDLINE    
During spermatogenesis, cell-cell actin-based adherens junctions (AJs), such as ectoplasmic specializations (ESs), between Sertoli and germ cells undergo extensive restructuring in the seminiferous epithelium to facilitate germ cell movement across the epithelium. Although the mechanism(s) that regulates AJ dynamics in the testis is virtually unknown, Rho GTPases have been implicated in the regulation of these events in other epithelia. Studies have shown that the in vitro assembly of the Sertoli-germ cell AJs but not of the Sertoli cell tight junctions (TJs) is associated with a transient but significant induction of RhoB. Immunohistochemistry has shown that the localization of RhoB in the seminiferous epithelium is stage specific, being lowest in stages VII-VIII prior to spermiation, and displays cell-specific association during the epithelial cycle. Throughout the cycle, RhoB was localized near the site of basal and apical ESs but was restricted to the periphery of the nuclei in elongating (but not elongated) spermatids, spermatocytes, and Sertoli cells. However, RhoB was not detected near the site of apical ESs at stages VII-VIII. Furthermore, disruption of AJs in Sertoli-germ cell cocultures either by hypotonic treatment or by treatment with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) also induced RhoB expression. When adult rats were treated with AF-2364 to perturb Sertoli-germ cell AJs in vivo, a approximately 4-fold induction in RhoB in the testis, but not in kidney and brain, was detected within 1 h, at least approximately 1-4 days before germ cell loss from the epithelium could be detected by histological analysis. The signaling pathway(s) by which AF-2364 perturbed the Sertoli-germ cell AJs apparently began with an initial activation of integrin, which in turn activated RhoB, ROCK1, (Rho-associated protein kinase 1, also called ROKbeta), LIMK1 (LIM kinase 1, also called lin-11 isl-1 mec3 kinase 1), and cofilin but not p140mDia and profilin via phosphorylation. Immunoprecipitation and immunoblots revealed that the induction of LIMK1 was mediated via an increase in its phospho-Ser but not phospho-Tyr content. Furthermore, Y-27632 ([(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane-carboxamide, 2HCl]), a specific ROCK inhibitor, could effectively delay the AF-2364-induced germ cell loss from the seminiferous epithelium in vivo, illustrating that the integrin/RhoB/ROCK/LIMK pathway indeed plays a crucial role in the regulation of Sertoli-germ cell AJ dynamics. The fact that the RhoB pathway in the kidney and brain was not activated suggests that AF-2364 exerts its effects primarily at the testis-specific ES multiprotein complex structures between Sertoli cells and spermatids. In summary, this report illustrates that Sertoli germ cell AJ dynamics are regulated, at least in part, via the integrin/ROCK/LIMK/cofilin signaling pathway.
Wing-yee Lui; Will M Lee; C Yan Cheng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2003-01-22
Journal Detail:
Title:  Biology of reproduction     Volume:  68     ISSN:  0006-3363     ISO Abbreviation:  Biol. Reprod.     Publication Date:  2003 Jun 
Date Detail:
Created Date:  2003-05-21     Completed Date:  2004-02-02     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0207224     Medline TA:  Biol Reprod     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2189-206     Citation Subset:  IM    
Population Council, Center for Biomedical Research, New York, New York 10021, USA.
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MeSH Terms
Adherens Junctions / drug effects,  physiology*
Amides / pharmacology
Brain / cytology,  metabolism
Cells, Cultured
Coculture Techniques
GTP Phosphohydrolases / metabolism*
Germ Cells / drug effects,  physiology*
Hydrazines / pharmacology
Indazoles / pharmacology
Intracellular Signaling Peptides and Proteins
Kidney / cytology,  metabolism
Protein-Serine-Threonine Kinases / antagonists & inhibitors,  physiology*
Pyridines / pharmacology
RNA, Messenger / biosynthesis
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Seminiferous Epithelium / cytology,  physiology
Sertoli Cells / drug effects,  physiology*
Signal Transduction / drug effects,  physiology*
Testis / cytology,  physiology*
rho-Associated Kinases
rhoB GTP-Binding Protein / metabolism*
Grant Support
Reg. No./Substance:
0/1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide; 0/Amides; 0/Hydrazines; 0/Indazoles; 0/Intracellular Signaling Peptides and Proteins; 0/Pyridines; 0/RNA, Messenger; 138381-45-0/Y 27632; EC Kinases; EC Kinases; EC 3.6.1.-/GTP Phosphohydrolases; EC GTP-Binding Protein

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