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Comment |
Oocyte-dependent activation of MTOR in cumulus cells controls the development and survival of cumulus-oocyte complexes. Guo J et al. (2016) Communication between oocytes and their companion somatic cells promotes the healthy development of ovarian follicles, which is crucial for producing fertilizable oocytes competent to support embryogenesis. However, how oocyte-derived signaling regulates these essential processes remains largely undefined. Here, we demonstrated that oocyte-derived paracrine factors, particularly GDF9 and GDF9:BMP15 heterodimer, promote the development and survival of cumulus-oocyte complexes (COCs) partly by suppressing the expression of Ddit4l, a negative regulator of MTOR, and enabling the activation of MTOR signaling in cumulus cells. Cumulus cells expressed less Ddit4l mRNA and protein than mural granulosa cells, which is in striking contrast to the expression of phosphorylated RPS6 (a major downstream effector of MTOR). Knockdown of Ddit4l activated MTOR signaling in cumulus cells, whereas inhibition of MTOR in COCs compromised oocyte developmental competence and cumulus cell survival, with the latter likely attributable to specific changes of a subset of transcripts in the transcriptome of COCs. Therefore, oocyte suppression of Ddit4l expression allows for MTOR activation in cumulus cells, and this oocyte-dependent activation of MTOR signaling in cumulus cells controls the development and survival of COCs.//////////////////
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Comment |
SSR 2010 Abstract 149. Mouse Oocytes Promote the Mechanistic Target of Rapamycin
(Serine/Threonine Kinase, MTOR) Pathway in Cumulus Cells by Suppressing
the Expression of DNA-damage-inducible Transcript 4-like (Ddit4l). You-Qiang
Su, Koji Sugiura, Karen Wigglesworth, and John J. Eppig. The Jackson Laboratory,
Bar Harbor, ME, USA
Mechanistic (also known as mammalian) target of rapamycin (MTOR) is an
evolutionally conserved kinase that plays an essential role in the control of cell
growth and development by integrating and transmitting multiple extracellular cues,
such as nutrient supply and signals of growth factor and stress. We reported
previously that mouse oocytes promote several key metabolic processes including
glycolysis, cholesterol biosynthesis and uptake of some amino acids in cumulus cells.
This suggests that mouse oocytes promote MTOR activity in cumulus cells, but this
implication had not been tested previously. Here, we show that mouse oocytes
promote the MTOR pathway in cumulus cells by suppressing expression of DNAdamage-
inducible transcript 4-like (Ddit4l) mRNA, a negative regulator of MTOR
pathway. In situ hybridization of Ddit4l mRNA revealed its robust expression in
mural granulosa cells, whereas expression in cumulus was significantly lower.
Removal of oocytes from cumulus-oocyte complexes (COCs) by oocytectomy
(OOX) caused dramatic up-regulation of Ddit4l mRNA in OOX cumulus cells,
suggesting that the lower level of expression of Ddit4l in cumulus cells is due to
suppression by oocytes. Coincident with up-regulation of Ddit4l expression, levels of
phosphorylated MTOR (p-MTOR) in OOX cumulus cells was reduced. Upregulation
of Ddit4l mRNA and down-regulation of p-MTOR in wild type (WT)
OOX cumulus cells was prevented by co-culture of these OOX cumulus cells with
WT, but not Bmp15-/- or Gdf9+/-Bmp15-/-, fully-grown, germinal vesicle stage
oocytes. This suggests that the regulatory effect of oocytes on MTOR pathway in
cumulus cells is mediated by oocyte-secreted factors, presumably, GDF9 and/or
BMP15. Indeed, Ddit4l mRNA was significantly up-regulated in Bmp15-/- and
Gdf9+/-Bmp15-/- cumulus cells; and treatment with recombinant GDF9 and/or BMP15
suppressed expression of Ddit4l mRNA in WT OOX cumulus cells. Recombinant
GDF9 and/or BMP15 were also found to promote the elevated level of p-MTOR in
OOX cumulus cells. Treatment with inhibitors of SMAD2/3 but not of SMAD3
dramatically up-regulated the level of Ddit4l mRNA in WT COCs, and blocked
GDF9-induced suppression of Ddit4l mRNA expression in WT OOX cumulus cells,
indicating that a SMAD2-dependent pathway is involved in the process of oocyte and
GDF9 regulation of MTOR pathway in cumulus. In conclusion, mouse oocytes, via
GDF9 and BMP15, promote the MTOR pathway in cumulus cells, at least in part, by
suppressing expression of Ddit4l, a negative regulator of this pathway.
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