Differential Regulation Ofspermatogenic Processby Lkb1 Isoforms In Mouse Testis

Liver serine/threonine kinase B1(LKB1),is a tumor suppressor associated with the pathogenesis of Peutz-Jeghers syndrome.Affected males are at increased risk of developing Sertoli cell tumors and display defective spermatogenesis.Male mice lacking the short isoform(Lkb1_S)of Lkb1 were sterile and exhibited abnormal spermiogenesis.In addition to the short isoform,the long isform of Lkb1(Lkb1_L)is also expressed in testis,however,the requirement of the long isoform for fertility and the functional difference between the two isoforms remain unknown.Herein,different from the spermiation failure reported in Lkb1_S knockout mice,conditional deletion(c KO)of both isoforms of Lkb1 in germ cells resulted in male sterility stemming from defects in acrosome formation,as well as nuclear elongation and condensation during spermatid differentiation.Additionally,Lkb1 c KO mice showed a progressive germ cell loss that was not observed with specific deletion of the Lkb1_S isoform.Further experiments revealed that the defect resulted from the failure of spermatogonial stem/progenitor cells(SPCs)maintenance.Moreover,increased m TORC1 activity and presence of p-rp S6-positive germ cells in postnatal c KO testes was consistent with a tendency toward germline stem cell differentiation.However,in vivo inhibition of the m TORC1 pathway through rapamycin treatment failed to rescue the loss of SPCs in c KO mice.These results suggest that LKB1 regulates the maintenance and survival of SPCs in an m TORC1 independent manner.In summary,our study supports different roles of Lkb1 isoforms in spermatogenesis with Lkb1_L directing SPCs maintenance,and Lkb1_Land Lkb1_S coordinately regulating spermatid differentiation.