Blood-testis barrier dynamics are regulated by {alpha}2-macroglobulin via the c-Jun N-terminal protein kinase pathway.
The blood-testis barrier (BTB), in contrast to the blood-brain and blood-retina barriers, is composed of coexisting tight junctions, gap junctions, and basal ectoplasmic specializations, a testis-specific type of adherens junction. Recent studies showed that BTB restructuring that facilitates germ cell migration during spermatogenesis involves proteolysis, an event that is usually restricted to the cell-matrix interface in other epithelia. For instance, a surge in alpha(2)-macroglobulin (alpha(2)-MG), a protease inhibitor produced by Sertoli cells, was detected at the Sertoli-Sertoli and Sertoli-germ cell interface in the epithelium during cadmium chloride-induced BTB disruption in adult rats. It is thus proposed that the increase in alpha(2)-MG is crucial for protecting the epithelium from unwanted proteolysis as well as regulating the availability of cytokines that affect junction turnover. Although both tight junction and adherens junction dynamics at the BTB are regulated via the p38 MAPK signaling pathway, the mechanism(s) that regulates alpha(2)-MG is entirely unknown. In this study, we have shown that by administering dimethylaminopurine, a c-Jun N-terminal protein kinase (JNK) inhibitor, to the testis, JNK activity was blocked specifically and alpha(2)-MG production was inhibited, worsening the cadmium chloride-induced damage to the epithelium. Studies coupled with inhibitors, immunoblottings, and immunofluorescent and electron microscopy have unequivocally demonstrated that the JNK signaling pathway is a putative regulatory pathway for alpha(2)-MG production in the testis. This finding illustrates for the first time that a cell-matrix restructuring event occurs in normal cell physiology at the cell-cell interface in the testis, highlighting the significance of alpha(2)-MG in the regulation of BTB function.
Wong
Ching-Hang
CH
Population Council, 1230 York Avenue, New York, New York 10021, USA.
Mruk
Dolores D
DD
Siu
Michelle K Y
MK
Cheng
C Yan
CY
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D019256:Cadmium Chloride / Q000633:toxicity; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012670:Seminiferous Epithelium / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*; D013737:Testis / Q000378:metabolism*; D000511:alpha-Macroglobulins / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000511:alpha-Macroglobulins; C001020:N(6),N(6)-dimethyladenine; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019256:Cadmium Chloride; D000225:Adenine