title: WNT/β-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary.
abstract: Sexual development is initiated through differentiation of testicular Sertoli cells or ovarian granulosa cells. Although these supporting cells are considered to develop from common bipotential precursors, recent evidence suggests that distinct supporting cell populations are present in the ovary, with one providing granulosa cells of the medullary follicles and the other providing granulosa cells of the cortical follicles, the latter of which support lifelong fertility. Here, we demonstrate that XX fetal gonads contain GATA4 expressing supporting cells that either enter mitotic arrest, or remain proliferative. Blocking WNT signalling reduces XX supporting cell proliferation, while stabilising β-catenin signalling promotes proliferation, indicating that the renewal of pre-granulosa cells is dependent on WNT/β-catenin signalling in the proliferative supporting cell population. In contrast, XX supporting cells express p27 and FOXL2 and are maintained in mitotic arrest. Although FOXL2 is required for maintaining high levels of p27 expression, it is dispensable for entry and maintenance of mitotic arrest in XX supporting cells. Combined our data suggest that both medullary and cortical precursors arise from a common GATA4 expressing cell type. In addition, this work indicates that a balance between supporting cell self-renewal and differentiation is maintained in the developing ovary by relative WNT/β-catenin and p27/FOXL2 activities. This study provides significant new insights into the origin and formation of ovarian follicles and evidence supporting a common fetal origin of medullary and cortical granulosa cells.
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research and Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Sonja E
authors.initials: SE
authors.lastname: Gustin
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research and Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hogg
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research and Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Stringer
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Raphael H
authors.initials: RH
authors.lastname: Rastetter
authors.affiliation: Laboratory of Genetics, National Institute on Aging, NIH-IRP, Baltimore, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Pelosi
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research and Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: Denise C
authors.initials: DC
authors.lastname: Miles
authors.affiliation: Murdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sinclair
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wilhelm
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research and Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia. Electronic address: patrick.western@hudson.org.au.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Western
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D060528:Wnt4 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C493961:Cdkn1b protein, mouse; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D060528:Wnt4 Protein; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: FOXL2; Follicle; Granulosa; Ovary; WNT4; β-catenin