Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Lats1 null mice displayed severe fertility defects with 60% showing complete sterility (St. Johns et al., 1999). Ovaries from null mice showed fewer follicles with mainly primary or secondary follicles. Formation of the antrum was much less prominent and there was no corpus luteum formation. The authors suggested an impairment of ovulation in these mice. Lats1-/- mice develop soft-tissue sarcomas and ovarian stromal cell tumours and are highly sensitive to carcinogenic treatments. It is likely expressed in granulosa, luteal and stromal cells (St. John et al., 1999).

Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Lats1 Deletion Causes Increased Germ Cell Apoptosis and Follicular Cysts in Mouse Ovaries. Sun T et al. (2015) The hippo signaling pathway is essential for regulating proliferation and apoptosis in mammalian cells. The LATS1 kinase is a core member of the hippo signaling pathway that phosphorylates and inactivates the transcriptional co-activators YAP1 and WWTR1. Deletion of Lats1 results in low neonate survival and ovarian stromal tumors in surviving adults, but the effects of Lats1 on early follicular development are not understood. Here, the expression of hippo pathway components were including Wwtr1, Stk4, Stk3, Lats2 and Yap1 transcripts were decreased by 50% in mouse ovaries between 2 and 8 days of age while expression was maintained from 8 days to 21 days and after priming with eCG. LATS1, LATS2, and MOB1B were localized to both germ and somatic cells of primordial to antral follicles. Interestingly, YAP1 was predominantly cytoplasmic, while WWTR1 was nuclear in oocytes and somatic cells. Deletion of Lats1 caused an increase in germ cell apoptosis from 1.7% in control ovaries to 3.6% in Lats1 mutant ovaries and a 58% and 32% decrease in primordial and activated follicle numbers in cultured mutant ovaries. Surprisingly, there was an increase in Bmp15, but not Gdf9, Figla, Nobox transcripts or somatic-specific transcripts Amh and Wnt4 in cultured Lats1 mutant ovaries. Lastly, Lats1 mutant ovaries developed ovarian cysts at a higher frequency (43%) compared to heterozygous (24%) and control ovaries (8%). The results show that the hippo pathway is active in ovarian follicles and that LATS1 is required to maintain the pool of germ cells and primordial follicles.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: Lats1 and Lats2 are required for ovarian granulosa cell fate maintenance. Tsoi M et al. (2019) Recent reports suggest that the Hippo signaling pathway influences ovarian follicle development; however, its exact roles remain unknown. Here, we examined the ovarian functions of the Hippo kinases large tumor suppressors (LATS)1 and 2, which serve to inactivate the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Inactivation of Lats1/2 in murine granulosa cells either in vitro or in vivo resulted in a loss of granulosa cell morphology, function, and gene expression. Mutant cells further underwent changes in structure and gene expression suggestive of epithelial-to-mesenchymal transition and transdifferentiation into multiple lineages. In vivo, granulosa cell-specific loss of Lats1/2 caused the ovarian parenchyma to be mostly replaced by bone tissue and seminiferous tubule-like structures. Transdifferentiation into Sertoli-like cells and osteoblasts was attributed in part to the increased recruitment of YAP and TAZ to the promoters of sex-determining region Y box 9 and bone γ-carboxyglutamate protein, key mediators of male sex determination and osteogenesis, respectively. Together, these results demonstrate for the first time a critical role for Lats1/2 in the maintenance of the granulosa cell genetic program and further highlight the remarkable plasticity of granulosa cells.-Tsoi, M., Morin, M., Rico, C., Johnson, R. L., Paquet, M., Gévry, N., Boerboom, D. Lats1 and Lats2 are required for ovarian granulosa cell fate maintenance.//////////////////

Species: mouse
Mutation name:
type: targeted overexpression
fertility: subfertile
Comment: SUMOylation activates large tumour suppressor 1 to maintain the tissue homeostasis during Hippo signalling. Mei L et al. (2021) Large tumour suppressor (LATS) 1/2, the core kinases of Hippo signalling, are critical for maintaining tissue homeostasis. Here, we investigate the role of SUMOylation in the regulation of LATS activation. High cell density induces the expression of components of the SUMOylation machinery and enhances the SUMOylation and activation of Lats1 but not Lats2, whereas genetic deletion of the SUMOylation E2 ligase, Ubc9, abolishes this Lats1 activation. Moreover, SUMOylation occurs at the K830 (mouse K829) residue to activate LATS1 and depends on the PIAS1/2 E3 ligase. Whereas the K830 deSUMOylation mutation of LATS1 found in the human metastatic prostate cancers eliminates the kinase activity by attenuating the formation of the phospho-MOB1/phospho-LATS1 complex. As a result, the LATS1(K830R) transgene phenocopies Yap transgene to cause the oversized livers in mice, whereas Lats1(K829R) knock-in phenocopies the deletion of Lats1 in causing the reproductive and endocrine defects and ovary tumours in mice. Thus, SUMOylation-mediated LATS1 activation is an integral component of Hippo signalling in the regulation of tissues homeostasis.//////////////////