Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction

The lats gene has been identified as a tumour suppressor in Drosophila mela nogaster using mosaic screens(1). Mosaic flies carrying somatic cells that are mutant for lats develop large tumours in many organs(1,2). The human LA TS1 homologue res cues embryonic lethality and inhibits tumour growth in la ts mutant flies, demonstrating the functional conservation of this gene(3). Biochemical and genetic analyses have revealed that LATS1 functions as a n egative regulator of CDC2 (ref. 3). These data suggest that mammalian LATS1 may have a role in tumorigenesis. To elucidate the function of mammalian L ATS1, we have generated Lats1(-/-) mice. Lats1(-/-) animals exhibit a lack of mammary grand development, infertility and growth retardation. Accompany ing these defects are hyperplastic changes in the pituitary and decreased s erum hormone levels. The reproductive hormone defects of Lats1(-/-) mice ar e reminiscent of isolated LH-hypogonadotropic hypogonadism and corpus luteu m insufficiency in humans. Furthermore, Lats1(-/-) mice develop soft-tissue sarcomas and ovarian stromal cell tumours and are highly sensitive to carc inogenic treatments. Our data demonstrate a role for Lats1 in mammalian tum origenesis and specific endocrine dysfunction.