Female infertility in PDE3A<sup>-/-</sup>mice

Shen, Weixing; Ahmad, Faiyaz; Hockman, Steven; Ma, John; Omi, Hitoshi; Raghavachari, Nalini; Manganiello, Vincent

doi:10.4161/cc.9.23.14090

Cited by 16 publications

(9 citation statements)

References 82 publications

(155 reference statements)

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“…The centrosome-associated protein MAPK was previously shown to be required for proper spindle formation during oocyte meiosis. 34,[38][39][40] Recent study showed Rho GTPase RhoA RNAi reduced the expression of p-MAPK and resulted in aberrant spindle formation during mouse oocyte meiotic maturation. 41 While our result showed FMNL1 depletion resulted in the disrupted localization and the decreased expression of p-MAPK, as Formin proteins are the effectors of Rho GTPases, our results indicated that similar with Rho GTPase RhoA, FMNL1 might regulate spindle formation during oocyte meiosis through its effects on p-MAPK expression.…”

Section: Discussionmentioning

confidence: 99%

RhoA-mediated FMNL1 regulates GM130 for actin assembly and phosphorylates MAPK for spindle formation in mouse oocyte meiosis

et al. 2015

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Formin-like 1 (FMNL1) is a member of Formin family proteins which are the actin nucleators. Although FMNL1 activities have been shown to be essential for cell adhesion, cytokinesis, cell polarization and migration in mitosis, the functional roles of mammalian FMNL1 during oocyte meiosis remain uncertain. In this study, we investigated the functions of FMNL1 in mouse oocytes using specific morpholino (MO) microinjection and live cell imaging. Immunofluorescent staining showed that in addition to its cytoplasmic distribution, FMNL1 was primarily localized at the spindle poles after germinal vesicle breakdown (GVBD). FMNL1 knockdown caused the low rate of polar body extrusion and resulted in large polar bodies. Time-lapse microscopic and immunofluorescence intensity analysis indicated that this might be due to the aberrant actin expression levels. Cortical polarity was disrupted as shown by a loss of actin cap and cortical granule free domain (CGFD) formation, which was confirmed by a failure of meiotic spindle positioning. And this might be the reason for the large polar body formation. Spindle formation was also disrupted, which might be due to the abnormal localization of p-MAPK. These results indicated that FMNL1 affected both actin dynamics and spindle formation for the oocyte polar body extrusion. Moreover, FMNL1 depletion resulted in aberrant localization and expression patterns of a cis-Golgi marker protein, GM130. Finally, we found that the small GTPase RhoA might be the upstream regulator of FMNL1. Taken together, our data indicate that FMNL1 is required for spindle organization and actin assembly through a RhoA-FMNL1-GM130 pathway during mouse oocyte meiosis.

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Section: Discussionmentioning

confidence: 99%

RhoA-mediated FMNL1 regulates GM130 for actin assembly and phosphorylates MAPK for spindle formation in mouse oocyte meiosis

et al. 2015

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“…It may be active 'initiation', or there may be 'release from inhibition' that propels spermatocytes out of meiotic prophase. For example, in Drosophila, Xenopus and mouse oocytes, inhibition of PLK1 maintains prophase arrest (Kishimoto, 2003;Shen et al, 2010;Xiang et al, 2007). Certainly both SC dynamics and repair of SPO11-induced DSBs involved in meiotic recombination must be coordinated for timely completion of meiotic prophase.…”

Section: Plk1 Desynapsis and Meiotic Prophase Exitmentioning

confidence: 99%

Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

Jordan

Karppinen

Handel

2012

Journal of Cell Science

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During meiosis, accurate coordination of the completion of homologous recombination and synaptonemal complex (SC) disassembly during the prophase to metaphase I (G2/MI) transition is essential to avoid aneuploid gametes and infertility. Previous studies have shown that kinase activity is required to promote meiotic prophase exit. The first step of the G2/MI transition is the disassembly of the central element components of the SC; however, the kinase(s) required to trigger this process remains unknown. Here we assess roles of polo-like kinases (PLKs) in mouse spermatocytes, both in vivo and during prophase exit induced ex vivo by the phosphatase inhibitor okadaic acid. All four PLKs are expressed during the first wave of spermatogenesis. Only PLK1 (not PLK2-4) localizes to the SC during the G2/MI transition. The SC central element proteins SYCP1, TEX12 and SYCE1 are phosphorylated during the G2/MI transition. However, treatment of pachytene spermatocytes with the PLK inhibitor BI 2536 prevented the okadaic-acid-induced meiotic prophase exit and inhibited phosphorylation of the central element proteins as well as their removal from the SC. Phosphorylation assays in vitro demonstrated that PLK1, but not PLK2-4, phosphorylates central element proteins SYCP1 and TEX12. These findings provide mechanistic details of the first stage of SC disassembly in mammalian spermatocytes, and reveal that PLK-mediated phosphorylation of central element proteins is required for meiotic prophase exit.

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“…3A-KO mice represent an in vivo model where meiotic maturation and ovulation are dissociated, and which underscores inhibition of PDE3A as a potential strategy for contraception. Recent studies by Shen et al (38) suggest that elevated cAMP/PKA signaling in 3A-KO oocytes prevents dephosphorylation and activation of MPF, a key regulator of G2/M transition and resumption of meosis, and maintains meotic arrest via PKA-catalyzed phosphorylation and inactivation of Cdc25B (39) and Polo-like kinase 1 (Plk1) (38). In WT oocytes, PKA catalytic subunit (PKAc) was rapidly translocated into the nucleus, and then to the spindle apparatus, but in 3A-KO oocytes, PKAc remained in the cytosol (38).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies by Shen et al (38) suggest that elevated cAMP/PKA signaling in 3A-KO oocytes prevents dephosphorylation and activation of MPF, a key regulator of G2/M transition and resumption of meosis, and maintains meotic arrest via PKA-catalyzed phosphorylation and inactivation of Cdc25B (39) and Polo-like kinase 1 (Plk1) (38). In WT oocytes, PKA catalytic subunit (PKAc) was rapidly translocated into the nucleus, and then to the spindle apparatus, but in 3A-KO oocytes, PKAc remained in the cytosol (38). Incubation of 3A-KO oocytes with PKA inhibitors reactivated MPF (37) and Plk1 (38), and resumed meiosis.…”

Section: Introductionmentioning

confidence: 99%

“…In WT oocytes, PKA catalytic subunit (PKAc) was rapidly translocated into the nucleus, and then to the spindle apparatus, but in 3A-KO oocytes, PKAc remained in the cytosol (38). Incubation of 3A-KO oocytes with PKA inhibitors reactivated MPF (37) and Plk1 (38), and resumed meiosis. PDE3A was found to be co-localized with Plk1 in WT oocytes, and co-immunoprecipitated with Plk1 in WT ovary and Hela cells.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility

Begum

Shen

Manganiello

2011

Current Opinion in Pharmacology

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Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at Go-G1 phase, which resulted from dysregulation of cAMP/Protein kinase A (PKA)- and Mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G2/M phase because increased cAMP/PKA signaling in KO oocytes most likely inhibits Cdc25B-catalyzed dephosphorylation/activation of Cdc2 (maturation promoting factor), a key regulator of G2/M transition.

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Female infertility in PDE3A^-/-mice

Cited by 16 publications

References 82 publications

RhoA-mediated FMNL1 regulates GM130 for actin assembly and phosphorylates MAPK for spindle formation in mouse oocyte meiosis

RhoA-mediated FMNL1 regulates GM130 for actin assembly and phosphorylates MAPK for spindle formation in mouse oocyte meiosis

Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility

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Female infertility in PDE3A-/-mice

Cited by 16 publications

References 82 publications

RhoA-mediated FMNL1 regulates GM130 for actin assembly and phosphorylates MAPK for spindle formation in mouse oocyte meiosis

RhoA-mediated FMNL1 regulates GM130 for actin assembly and phosphorylates MAPK for spindle formation in mouse oocyte meiosis

Polo-like kinase is required for synaptonemal complex disassembly and phosphorylation in mouse spermatocytes

Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility

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Female infertility in PDE3A^-/-mice