title: Multiple Mechanisms Cooperate to Constitutively Exclude the Transcriptional Co-Activator YAP from the Nucleus During Murine Oogenesis.
abstract: Reproduction depends on the generation of healthy oocytes. Improving therapeutic strategies to prolong or rescue fertility depends on identifying the inter- and intracellular mechanisms that direct oocyte development under physiological conditions. Growth and proliferation of multiple cell types is regulated by the Hippo signaling pathway, whose chief effectors are the transcriptional co-activator YAP and its paralogue WWTR1. To resolve conflicting results concerning the potential role of Hippo in mammalian oocyte development, we systematically investigated the expression and localization of YAP in mouse oocytes. We report that that YAP is expressed in the germ cells beginning as early as Embryonic Day 15.5 and subsequently throughout pre- and postnatal oocyte development. However, YAP is restricted to the cytoplasm at all stages. YAP is phosphorylated at serine-112 in growing and fully grown oocytes, identifying a likely mechanistic basis for its nuclear exclusion, and becomes dephosphorylated at this site during meiotic maturation. Phosphorylation at serine-112 is regulated by a mechanism dependent on cyclic AMP and protein kinase A, which is known to be active in oocytes prior to maturation. Growing oocytes also contain a subpopulation of YAP, likely dephosphorylated, that is able enter the oocyte nucleus, but it is not retained there, implying that oocytes lack the cofactors required to retain YAP in the nucleus. Thus, although YAP is expressed throughout oocyte development, phosphorylation-dependent and -independent mechanisms cooperate to ensure that it does not accumulate in the nucleus. We conclude that nuclear YAP does not play a significant physiological role during oocyte development in mammals.
authors.affiliation: Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Canada Division of Experimental Medicine, McGill University Health Centre, Montreal, Canada Research Institute of the McGill University Health Centre, Montreal, Canada.
authors.forename: Laleh
authors.initials: L
authors.lastname: Abbassi
authors.affiliation: Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland.
authors.forename: Safia
authors.initials: S
authors.lastname: Malki
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Canada.
authors.forename: Katie
authors.initials: K
authors.lastname: Cockburn
authors.affiliation: Département des sciences animales, Université Laval, Québec, Canada.
authors.forename: Angus
authors.initials: A
authors.lastname: Macaulay
authors.affiliation: Département des sciences animales, Université Laval, Québec, Canada.
authors.forename: Claude
authors.initials: C
authors.lastname: Robert
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Canada.
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.affiliation: Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Canada Division of Experimental Medicine, McGill University Health Centre, Montreal, Canada Department of Biology, McGill University, McGill University Health Centre, Montreal, Canada Research Institute of the McGill University Health Centre, Montreal, Canada hugh.clarke@mcgill.ca.
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Clarke
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D009865:Oocytes / Q000502:physiology; D009866:Oogenesis / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D011247:Pregnancy; D021381:Protein Transport / Q000235:genetics; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse
keywords: Hippo; YAP; fertility; intracellular localization; oocyte; oogenesis