Oocyte-dependent activation of MTOR in cumulus cells controls the development and survival of cumulus-oocyte complexes

Abstract

Communication between oocytes and their companion somatic cells promotes the healthy development of ovarian follicles, which is crucial for producing oocytes that can be fertilized and are competent to support embryogenesis. However, how oocyte-derived signaling regulates these essential processes remains largely undefined. Here, we demonstrate that oocyte-derived paracrine factors, particularly GDF9 and GDF9-BMP15 heterodimer, promote the development and survival of cumulus-cell-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 to be attributable to specific changes in 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.

Ascorbic acid induces global epigenetic reprogramming to promote meiotic maturation and developmental competence of porcine oocytes

“…Ascorbic acid was also shown to improve blastocyst development of porcine hand-cloned embryos mainly through the antioxidant pathway 29 . Evidences showed that oocyte-derived BMP15 could regulate the proliferation, apoptosis 34 and extension 35 of cumulus cells to affect quality and subsequent development of oocytes 36 . In porcine, 100 ng/ml BMP15 added individually into in vitro maturation medium of COCs did not change nuclear maturation rate of oocytes but did activate M-phase-promoting factor (MPF) and mitogen-activated protein kinase (MAPK) signals in oocytes 35 .…”

Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice

“…These analyses and follicle count were carried out as described previously ( 15 , 53 – 56 ) and are detailed, along with information about the antibodies used, in SI Appendix .…”

“…It controls myriad life processes by linking extra- and intracellular cues from nutrients, stress, growth factors, and hormones, and its dysfunction is associated with an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration ( 12 – 14 ). In mouse ovarian follicles, the MTOR pathway is selectively activated in cumulus cells, the granulosa cells surrounding oocytes, before ovulation induction, and this specific activation is partially attributable to oocyte-suppressing expression of Ddit4l , a negative regulator of MTOR ( 15 ). This oocyte-enabled activation of MTOR is crucial for the development and survival of both cumulus cells and oocytes ( 15 ).…”

“…In mouse ovarian follicles, the MTOR pathway is selectively activated in cumulus cells, the granulosa cells surrounding oocytes, before ovulation induction, and this specific activation is partially attributable to oocyte-suppressing expression of Ddit4l , a negative regulator of MTOR ( 15 ). This oocyte-enabled activation of MTOR is crucial for the development and survival of both cumulus cells and oocytes ( 15 ). Mtor is also robustly expressed in oocytes; however, its function, especially its specific roles in the control of coordinated development and function of oocytes and granulosa cells, was unknown.…”

Interference with the C-terminal structure of MARF1 causes defective oocyte meiotic division and female infertility in mice

“…Sperms were collected from caudal epididymides of 10-week-old B6D2F1 male mice with normal fertility, and were capacitated for 1 hour at 37°C in an incubator infused with 5%O 2 , 5%CO 2 and 90%N 2 . In vitro fertilization (IVF) was then carried out as described previously [ 12 ] . The formation of 2-cell and blastocyst-stage embryos was assessed 24 hours and 96 hours after IVF.…”