Kaisman-Elbaz Tehila, Sekler Israel, Fishman Daniel, Karol Nataly, Forberg Michal, Kahn Nicole, Hershfinkel Michal, Silverman William F
Department of Morphology, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, Israel.
J Cell Physiol. 2009 Jul;220(1):222-9. doi: 10.1002/jcp.21754.
Sertoli cells, lining the walls of the seminiferous tubules, are in close contact with and regulate all aspects of the development of the germ cells. Clusterin, is a glycoprotein produced abundantly by Sertoli cells, and associated with either apoptosis or cell survival. Zinc is present in high concentrations in the testis and required for sperm development by an as yet unknown mechanism. Permeation of zinc into cells via voltage-gated calcium channels (VGCCs), however, is suggested to induce cell death. We examined the possibility that Zn(2+) acts via clusterin to regulate germ cell survival. Employing an ex vivo model of mouse testis, we have assessed the role of permeation of heavy metal ions on clusterin production and secretion. Up-regulation of clusterin expression and its secretion was observed after a short exposure to zinc or to cadmium under depolarizing conditions. Expression of zinc transporter-1 (ZnT-1), previously shown to regulate Zn(2+) influx, increased following prolonged application of zinc or cadmium to the explants and prevented clusterin up-regulation by subsequent exposure to these ions. Inhibition of the MAPK and PI3K pathways reduced the up-regulation of clusterin following the intracellular rise of Zn(2+) or Cd(2+). Neutralization of secreted clusterin by an antibody or attenuation of clusterin up-regulation by inhibition of Zn(2+) permeation via the LTCC, reduced cell death in cultured seminiferous tubule cells. Taken together, our results indicate that Zn(2+) and Cd(2+) influx induce expression and secretion of clusterin, thereby linking metal homeostasis and germ cell fate.
支持细胞排列在生精小管壁上，与生殖细胞的发育各方面密切接触并进行调节。簇集素是一种由支持细胞大量产生的糖蛋白，与细胞凋亡或细胞存活相关。锌在睾丸中含量很高，通过一种尚不清楚的机制参与精子发育。然而，锌通过电压门控钙通道（VGCCs）进入细胞被认为会诱导细胞死亡。我们研究了锌离子是否通过簇集素调节生殖细胞存活的可能性。利用小鼠睾丸的体外模型，我们评估了重金属离子渗透对簇集素产生和分泌的作用。在去极化条件下短暂暴露于锌或镉后，观察到簇集素表达及其分泌上调。锌转运体-1（ZnT-1）的表达先前已被证明可调节锌离子内流，在将锌或镉长时间应用于外植体后其表达增加，并阻止随后暴露于这些离子时簇集素的上调。抑制丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3激酶（PI3K）途径可减少锌离子或镉离子细胞内升高后簇集素的上调。用抗体中和分泌的簇集素或通过抑制锌离子经L型钙通道（LTCC）的渗透来减弱簇集素上调，可减少培养的生精小管细胞的死亡。综上所述，我们的结果表明锌离子和镉离子内流诱导簇集素的表达和分泌，从而将金属稳态与生殖细胞命运联系起来。
