Differential interactions between transforming growth factor-beta3/TbetaR1, TAB1, and CD2AP disrupt blood-testis barrier and Sertoli-germ cell adhesion.
The biochemical basis that regulates the timely and selective opening of the blood-testis barrier (BTB) to migrating preleptotene/leptotene spermatocytes at stage VIII of the epithelial cycle in adult rat testes is virtually unknown. Recent studies have shown that cytokines (e.g. transforming growth factor (TGF)-beta3) may play a crucial role in this event. However, much of this information relies on the use of toxicants (e.g. CdCl(2)), making it difficult to relay these findings to normal testicular physiology. Here we report that overexpression of TGF-beta3 in primary Sertoli cells cultured in vitro indeed perturbed the tight junction (TJ) barrier with a concomitant decline in the production of BTB constituent proteins as follows: occludin, N-cadherin, and ZO-1. Additionally, local administration of TGF-beta3 to testes in vivo was shown to reversibly perturb the BTB integrity and Sertoli-germ cell adhesion via the p38 MAPK and ERK signaling pathways. Most importantly, the simultaneous activation of p38 and ERK signaling pathways is dependent on the association of the TGF-beta3-TbetaR1 complex with adaptors TAB1 and CD2AP because if TbetaR1 was associated preferentially with CD2AP, only Sertoli-germ cell adhesion was perturbed without compromising the BTB. Collectively, these data illustrate that local production of TGF-beta3, and perhaps other TGF-betas and cytokines, by Sertoli and germ cells into the microenvironment at the BTB during spermatogenesis transiently perturbs the BTB and Sertoli-germ cell adhesion to facilitate germ cell migration when the activated TbetaRI interacts with adaptors TAB1 and CD2AP. However, TGF-beta3 selectively disrupts Sertoli-germ cell adhesion in the seminiferous epithelium to facilitate germ cell migration without compromising BTB when TbetaRI interacts only with adaptor CD2AP.
Xia
Weiliang
W
Population Council, Center for Biomedical Research, 1230 York Avenue, New York, NY 10021, USA.
Mruk
Dolores D
DD
Lee
Will M
WM
Cheng
C Yan
CY
D030201:Activin Receptors, Type I / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005854:Germ Cells / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012671:Seminiferous Tubules / Q000378:metabolism; D012708:Sertoli Cells / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053782:Transforming Growth Factor beta3
D033942:Adaptor Proteins, Vesicular Transport; D047908:Intracellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; C099510:TAB1 protein, MAPKKK activator, vertebrate; C509046:Tgfb3 protein, rat; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat