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Somatic cells regulate maternal mRNA translation and developmental competence of mouse oocytes.

Chen J, Torcia S, Xie F, Lin CJ, Cakmak H, Franciosi F, Horner K, Onodera C, Song JS, Cedars MI, Ramalho-Santos M, Conti M - Nat. Cell Biol. (2013)

Bottom Line: Translation of specific maternal transcripts increases in oocytes cultured in association with somatic cells and is sensitive to EGF-like growth factors that act only on the somatic compartment.These somatic cell signals that affect translation require activation of the PI(3)K-AKT-mTOR pathway.Thus, mRNA translation depends on somatic cell cues that are essential to reprogramme the oocyte for embryo development.

View Article: PubMed Central - PubMed

Affiliation: 1] Center for Reproductive Sciences, University of California, San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA [3] Department of Obstetrics and Gynecology and Reproductive Sciences, University of California, San Francisco, California 94143, USA.

ABSTRACT
Germ cells divide and differentiate in a unique local microenvironment under the control of somatic cells. Signals released in this niche instruct oocyte reentry into the meiotic cell cycle. Once initiated, the progression through meiosis and the associated programme of maternal messenger RNA translation are thought to be cell autonomous. Here we show that translation of a subset of maternal mRNAs critical for embryo development is under the control of somatic cell inputs. Translation of specific maternal transcripts increases in oocytes cultured in association with somatic cells and is sensitive to EGF-like growth factors that act only on the somatic compartment. In mice deficient in amphiregulin, decreased fecundity and oocyte developmental competence is associated with defective translation of a subset of maternal mRNAs. These somatic cell signals that affect translation require activation of the PI(3)K-AKT-mTOR pathway. Thus, mRNA translation depends on somatic cell cues that are essential to reprogramme the oocyte for embryo development.

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Compromised developmental competence of oocytes from Areg−/−miceA. Summary of offspring from mating of wild type, Areg +/−, and Areg−/− mice. The number of litters is reported below the scatterplot. T test: **** p<0.0001 vs. WT. B. Bars represent the mean ± SEM of the two cell-embryo yield after in vitro fertilization (IVF) using CEOs from super-ovulated wild type and Areg−/− mice. T test: *** p<0.0001 vs. WT. The number of IVF experiments performed is reported below the bars. The number in parenthesis indicates the number mice used. C. After superovulation, a group of MII CEOs was stripped of cumulus cells and used for IVF. Bars represent the mean ± SEM of two cell-embryo yield. T test: *** p<0.001 vs. WT. The number of IVF experiment performed is reported below the bars. D. Bars represent the mean ± SEM of two cell embryo yield of wild type CEOs harvested from PMSG treated mice, cultured in vitro in the absence or presence of AREG for 12 hr until they had reached the MII stage and then used for IVF. T test:* p<0.05 vs. WT. E. Representative spindles from wild type and MII Areg−/− oocytes derived from superovulated CEO. Bar corresponds to 10 μm. F. Incidence of aberrant spindle formation n WT and Areg−/− oocytes; Bars represent the mean ± SEM of 3 experiments. paired T test: * p<0.05 vs. WT. See Supplementary Table S3 for statistics source data.
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Figure 3: Compromised developmental competence of oocytes from Areg−/−miceA. Summary of offspring from mating of wild type, Areg +/−, and Areg−/− mice. The number of litters is reported below the scatterplot. T test: **** p<0.0001 vs. WT. B. Bars represent the mean ± SEM of the two cell-embryo yield after in vitro fertilization (IVF) using CEOs from super-ovulated wild type and Areg−/− mice. T test: *** p<0.0001 vs. WT. The number of IVF experiments performed is reported below the bars. The number in parenthesis indicates the number mice used. C. After superovulation, a group of MII CEOs was stripped of cumulus cells and used for IVF. Bars represent the mean ± SEM of two cell-embryo yield. T test: *** p<0.001 vs. WT. The number of IVF experiment performed is reported below the bars. D. Bars represent the mean ± SEM of two cell embryo yield of wild type CEOs harvested from PMSG treated mice, cultured in vitro in the absence or presence of AREG for 12 hr until they had reached the MII stage and then used for IVF. T test:* p<0.05 vs. WT. E. Representative spindles from wild type and MII Areg−/− oocytes derived from superovulated CEO. Bar corresponds to 10 μm. F. Incidence of aberrant spindle formation n WT and Areg−/− oocytes; Bars represent the mean ± SEM of 3 experiments. paired T test: * p<0.05 vs. WT. See Supplementary Table S3 for statistics source data.

Mentions: To determine whether this somatic effect on oocyte translation occurs also in vivo and whether global translation is affected, genetic mouse models perturbing the EGF network were investigated. We have reported that the EGF-like growth factors AREG, EREG and BTC are induced by LH at the time of ovulation and that transactivation of EGFR is indispensable for oocyte maturation and ovulation11, 13. Whereas inactivation of EGFR causes a block in oocyte maturation in vivo and defective ovulation11, Areg−/− mice ovulate and are fertile11 but litter size is significantly decreased (Fig. 3A). When fertilization rates were assessed in vitro, CEOs or denuded oocytes derived from Areg−/− mice fertilize at a rate significantly lower than wild type (WT) littermates, suggesting a defect in developmental competence (Fig. 3B and C). Identical to the Areg−/− follicle activated in vivo, isolated CEOs from wild type mice cultured in vitro are not exposed to AREG. Therefore, the role of AREG in promoting cytoplasmic maturation was further tested by adding exogenous AREG during WT CEO in vitro maturation. This treatment improved their fertilization rate (Fig.3D), a finding consistent with other studies demonstrating positive effects of EGF network on developmental competence26-28.


Somatic cells regulate maternal mRNA translation and developmental competence of mouse oocytes.

Chen J, Torcia S, Xie F, Lin CJ, Cakmak H, Franciosi F, Horner K, Onodera C, Song JS, Cedars MI, Ramalho-Santos M, Conti M - Nat. Cell Biol. (2013)

Compromised developmental competence of oocytes from Areg−/−miceA. Summary of offspring from mating of wild type, Areg +/−, and Areg−/− mice. The number of litters is reported below the scatterplot. T test: **** p<0.0001 vs. WT. B. Bars represent the mean ± SEM of the two cell-embryo yield after in vitro fertilization (IVF) using CEOs from super-ovulated wild type and Areg−/− mice. T test: *** p<0.0001 vs. WT. The number of IVF experiments performed is reported below the bars. The number in parenthesis indicates the number mice used. C. After superovulation, a group of MII CEOs was stripped of cumulus cells and used for IVF. Bars represent the mean ± SEM of two cell-embryo yield. T test: *** p<0.001 vs. WT. The number of IVF experiment performed is reported below the bars. D. Bars represent the mean ± SEM of two cell embryo yield of wild type CEOs harvested from PMSG treated mice, cultured in vitro in the absence or presence of AREG for 12 hr until they had reached the MII stage and then used for IVF. T test:* p<0.05 vs. WT. E. Representative spindles from wild type and MII Areg−/− oocytes derived from superovulated CEO. Bar corresponds to 10 μm. F. Incidence of aberrant spindle formation n WT and Areg−/− oocytes; Bars represent the mean ± SEM of 3 experiments. paired T test: * p<0.05 vs. WT. See Supplementary Table S3 for statistics source data.
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Related In: Results  -  Collection

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Figure 3: Compromised developmental competence of oocytes from Areg−/−miceA. Summary of offspring from mating of wild type, Areg +/−, and Areg−/− mice. The number of litters is reported below the scatterplot. T test: **** p<0.0001 vs. WT. B. Bars represent the mean ± SEM of the two cell-embryo yield after in vitro fertilization (IVF) using CEOs from super-ovulated wild type and Areg−/− mice. T test: *** p<0.0001 vs. WT. The number of IVF experiments performed is reported below the bars. The number in parenthesis indicates the number mice used. C. After superovulation, a group of MII CEOs was stripped of cumulus cells and used for IVF. Bars represent the mean ± SEM of two cell-embryo yield. T test: *** p<0.001 vs. WT. The number of IVF experiment performed is reported below the bars. D. Bars represent the mean ± SEM of two cell embryo yield of wild type CEOs harvested from PMSG treated mice, cultured in vitro in the absence or presence of AREG for 12 hr until they had reached the MII stage and then used for IVF. T test:* p<0.05 vs. WT. E. Representative spindles from wild type and MII Areg−/− oocytes derived from superovulated CEO. Bar corresponds to 10 μm. F. Incidence of aberrant spindle formation n WT and Areg−/− oocytes; Bars represent the mean ± SEM of 3 experiments. paired T test: * p<0.05 vs. WT. See Supplementary Table S3 for statistics source data.
Mentions: To determine whether this somatic effect on oocyte translation occurs also in vivo and whether global translation is affected, genetic mouse models perturbing the EGF network were investigated. We have reported that the EGF-like growth factors AREG, EREG and BTC are induced by LH at the time of ovulation and that transactivation of EGFR is indispensable for oocyte maturation and ovulation11, 13. Whereas inactivation of EGFR causes a block in oocyte maturation in vivo and defective ovulation11, Areg−/− mice ovulate and are fertile11 but litter size is significantly decreased (Fig. 3A). When fertilization rates were assessed in vitro, CEOs or denuded oocytes derived from Areg−/− mice fertilize at a rate significantly lower than wild type (WT) littermates, suggesting a defect in developmental competence (Fig. 3B and C). Identical to the Areg−/− follicle activated in vivo, isolated CEOs from wild type mice cultured in vitro are not exposed to AREG. Therefore, the role of AREG in promoting cytoplasmic maturation was further tested by adding exogenous AREG during WT CEO in vitro maturation. This treatment improved their fertilization rate (Fig.3D), a finding consistent with other studies demonstrating positive effects of EGF network on developmental competence26-28.

Bottom Line: Translation of specific maternal transcripts increases in oocytes cultured in association with somatic cells and is sensitive to EGF-like growth factors that act only on the somatic compartment.These somatic cell signals that affect translation require activation of the PI(3)K-AKT-mTOR pathway.Thus, mRNA translation depends on somatic cell cues that are essential to reprogramme the oocyte for embryo development.

View Article: PubMed Central - PubMed

Affiliation: 1] Center for Reproductive Sciences, University of California, San Francisco, California 94143, USA [2] Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA [3] Department of Obstetrics and Gynecology and Reproductive Sciences, University of California, San Francisco, California 94143, USA.

ABSTRACT
Germ cells divide and differentiate in a unique local microenvironment under the control of somatic cells. Signals released in this niche instruct oocyte reentry into the meiotic cell cycle. Once initiated, the progression through meiosis and the associated programme of maternal messenger RNA translation are thought to be cell autonomous. Here we show that translation of a subset of maternal mRNAs critical for embryo development is under the control of somatic cell inputs. Translation of specific maternal transcripts increases in oocytes cultured in association with somatic cells and is sensitive to EGF-like growth factors that act only on the somatic compartment. In mice deficient in amphiregulin, decreased fecundity and oocyte developmental competence is associated with defective translation of a subset of maternal mRNAs. These somatic cell signals that affect translation require activation of the PI(3)K-AKT-mTOR pathway. Thus, mRNA translation depends on somatic cell cues that are essential to reprogramme the oocyte for embryo development.

Show MeSH
Related in: MedlinePlus