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Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis

Pradeep S Tanwar1, Tomoko Kaneko-Tarui, LiHua Zhang

  • 1Vincent Center For Reproductive Biology/Thier 931, Department of Obstetrics, Gynecology and Reproductive Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Human Molecular Genetics
|July 14, 2012
PubMed

Insights

Liver Kinase B1 (LKB1) signaling is crucial for male fertility. Loss of LKB1 in mice causes germ cell loss and testicular defects, mimicking Peutz-Jeghers syndrome (PJS) phenotypes.

Area of Science:

  • Reproductive biology
  • Molecular genetics
  • Cancer biology

Background:

  • Peutz-Jeghers syndrome (PJS) is linked to male infertility and Sertoli cell tumors.
  • Mutations in the Liver Kinase B1 (LKB1/STK11) gene are implicated in PJS and sporadic testicular cancers.
  • The role of LKB1 signaling in testicular function remains unclear.

Purpose of the Study:

  • To investigate the function of LKB1 signaling in Sertoli cells and testicular biology.
  • To elucidate the molecular mechanisms underlying testicular defects in PJS patients.

Main Methods:

  • Conditional deletion of the Lkb1 gene in somatic testicular cells of mice (Lkb1(cko)).
  • Analysis of testicular histology, germ cell development, and Sertoli cell function.
  • Assessment of signaling pathways including AMP kinase and mammalian target of rapamycin (mTOR).

Main Results:

  • Lkb1(cko) mice exhibited progressive germ cell loss and Sertoli cell-only tubules after 10 weeks.
  • Defects in Sertoli cell polarity, testicular junctional complexes, and kinase activation were observed.
  • Suppression of AMP kinase and activation of mTOR signaling were noted in Lkb1(cko) testes.
  • Loss of Tsc1/Tsc2 mimicked the Lkb1(cko) phenotype, implicating mTOR dysregulation.

Conclusions:

  • LKB1 signaling is essential for maintaining testicular structure and function in males.
  • Dysregulated mTOR signaling contributes to the testicular pathology seen in PJS.
  • This study provides insights into the molecular basis of testicular defects in PJS.

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