A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis

Abstract

LKB1 was discovered as a tumour suppressor mutated in Peutz-Jeghers syndrome, and is a gene involved in cell polarity as well as an upstream protein kinase for members of the AMP-activated protein kinase family. We report that mammals express two splice variants caused by alternate usage of 3′-exons. LKB1L is the previously described form, while LKB1s is a novel form in which the last 63 residues are replaced by a unique 39-residue sequence lacking known phosphorylation (Ser431) and farnesylation (Cys433) sites. Both isoforms are widely expressed in rodent and human tissues, although LKB1s is particularly abundant in haploid spermatids in the testis. Male mice in which expression of Lkb1s is knocked out are sterile, with the number of mature spermatozoa in the epididymis being dramatically reduced, and those spermatozoa that are produced have heads with an abnormal morphology and are non-motile. These results identify a previously undetected variant of LKB1, and suggest that it has a crucial role in spermiogenesis and male fertility.