TY - JOUR
T1 - Lats1 and Lats2 are required for ovarian granulosa cell fate maintenance
AU - Tsoi, Mayra
AU - Morin, Martin
AU - Rico, Charlène
AU - Johnson, Randy L.
AU - Paquet, Marilène
AU - Gévry, Nicolas
AU - Boerboom, Derek
N1 - Funding Information:
The authors thank Claude Paquet, Philippe Godin, and Meggie Girard (all from Université de Montréal) for technical support. The authors thank Jan Gossen (Osteo-Pharma, Oss, The Netherlands) for CYP19-cre mice. The authors thank McGill University and G↨nome Québec Innovation Centre (Montréal, QC, Canada) and the Canadian Center for Computational Genomics (C3G; Montréal, QC, Canada) for generating and analyzing microarray data. C3G is a node of the Canadian Genomic Innovation Network and is supported by the Canadian government through Genome Canada. The authors thank Dagmar Wilhelm (University of Melbourne, Parkville, VIC, Australia) for the FOXL2 antibody. The authors thank the Ligand Assay and Analysis Core at the University of Virginia (Charlottesville, VA, USA) for the hormonal measurements. This work was supported by Canadian Institutes of Health Research (CIHR) operating Grant MOP-142445 (to D.B.). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by U.S. National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development Specialized Cooperative Centers Program in Reproduction Research (SCCPRR) Grant U54-HD28934. M.T. was supported by a doctoral research award from the Fonds de Recherche du Québec-Santé (FRQS). The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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 Lαts2 are required for ovarian granulosa cell fate maintenance. FASEB J. 33, 10819–10832 (2019). www.fasebj.org.
AB - 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 Lαts2 are required for ovarian granulosa cell fate maintenance. FASEB J. 33, 10819–10832 (2019). www.fasebj.org.
KW - Bglap
KW - Hippo
KW - RUNX2
KW - Sox9
KW - transdifferentiation
UR - http://www.scopus.com/inward/record.url?scp=85072717404&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072717404&partnerID=8YFLogxK
U2 - 10.1096/fj.201900609R
DO - 10.1096/fj.201900609R
M3 - Article
C2 - 31268774
AN - SCOPUS:85072717404
SN - 0892-6638
VL - 33
SP - 10819
EP - 10832
JO - FASEB Journal
JF - FASEB Journal
IS - 10
ER -