ABSTRACT
Bidirectional communication between oocytes and the companion granulosa cells is essential
for the development and functions of both compartments. Oocytes are deficient in their
ability to transport certain amino acids and in carrying out glycolysis and cholesterol
biosynthesis. Cumulus cells must provide them with the specific amino acids and the
products in these metabolic pathways. Oocytes control metabolic activities in cumulus
cells by promoting the expression of genes in cumulus cells encoding specific amino
acid transporters and enzymes essential for the oocyte-deficient metabolic processes.
Hence oocytes outsource metabolic functions to cumulus cells to compensate for oocyte
metabolic deficiencies. Oocyte control of granulosa cell metabolism may also participate
in regulating the rate of follicular development in coordination with endocrine, paracrine,
and autocrine signals. Oocytes influence granulosa cell development mainly by secretion
of paracrine factors, although juxtacrine signals probably also participate. Key oocyte-derived
paracrine factors include growth differentiation factor 9, bone morphogenetic protein
15, and fibroblast growth factor 8B.
KEYWORDS
Oocytes - cumulus cells - metabolisms - oocyte-derived factors
REFERENCES
- 1
Eppig J J.
Oocyte control of ovarian follicular development and function in mammals.
Reproduction.
2001;
122
829-838
- 2
Buccione R, Schroeder A C, Eppig J J.
Interactions between somatic cells and germ cells throughout mammalian oogenesis.
Biol Reprod.
1990;
43
543-547
- 3 Eppig J J, Viveiros M M, Marin Bivens C, De La Fuente R.
Regulation of Mammalian Oocyte Maturation. In: Leung PCK, Adashi EY The Ovary. San Diego, CA; Elsevier Academic Press 2004:
113-129
- 4
Soyal S M, Amleh A, Dean J.
FIGα, a germ cell-specific transcription factor required for ovarian follicle formation.
Development.
2000;
127(21)
4645-4654
- 5
Reddy P, Liu L, Adhikari D et al..
Oocyte-specific deletion of Pten causes premature activation of the primordial follicle
pool.
Science.
2008;
319(5863)
611-613
- 6
Diaz F J, Wigglesworth K, Eppig J J.
Oocytes are required for the preantral granulosa cell to cumulus cell transition in
mice.
Dev Biol.
2007;
305(1)
300-311
- 7
Diaz F J, Wigglesworth K, Eppig J J.
Oocytes determine cumulus cell lineage in mouse ovarian follicles.
J Cell Sci.
2007;
120(Pt 8)
1330-1340
- 8
Dong J, Albertini D F, Nishimori K et al..
Growth differentiation factor-9 is required during early ovarian folliculogenesis.
Nature.
1996;
383
531-535
- 9
Galloway S M, McNatty K P, Cambridge L M et al..
Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation
rate and infertility in a dosage-sensitive manner.
Nat Genet.
2000;
25(3)
279-283
- 10
Latham K E, Wigglesworth K, McMenamin M, Eppig J J.
Stage-dependent effects of oocytes and growth differentiation factor 9 on mouse granulosa
cell development: advance programming and subsequent control of the transition from
preantral secondary follicles to early antral tertiary follicles.
Biol Reprod.
2004;
70(5)
1253-1262
- 11
Orisaka M, Orisaka S, Jiang J Y et al..
Growth differentiation factor 9 is antiapoptotic during follicular development from
preantral to early antral stage.
Mol Endocrinol.
2006;
20(10)
2456-2468
- 12
Gilchrist R B, Morrissey M P, Ritter L J, Armstrong D T.
Comparison of oocyte factors and transforming growth factor-beta in the regulation
of DNA synthesis in bovine granulosa cells.
Mol Cell Endocrinol.
2003;
201(1–2)
87-95
- 13
Gilchrist R B, Ritter L J, Armstrong D G.
Growth-promoting activity of mouse oocytes is developmentally regulated.
Biol Reprod.
2000;
62(suppl 1)
422
- 14
Gilchrist R B, Ritter L J, Armstrong D G.
Mouse oocyte mitogenic activity is developmentally coordinated throughout folliculogenesis
and meiotic maturation.
Dev Biol.
2001;
240
289-298
- 15
Otsuka F, Moore R K, Wang X et al..
Essential role of the oocyte in estrogen amplification of follicle-stimulating hormone
signaling in granulosa cells.
Endocrinology.
2005;
146(8)
3362-3367
- 16
Otsuka F, Yao Z, Lee T et al..
Bone morphogenetic protein-15. Identification of target cells and biological functions.
J Biol Chem.
2000;
275(50)
39523-39528
- 17
Vanderhyden B C, Telfer E E, Eppig J J.
Mouse oocytes promote proliferation of granulosa cells from preantral and antral follicles
in vitro.
Biol Reprod.
1992;
46
1196-1204
- 18
Vitt U A, Hayashi M, Klein C, Hsueh A J.
Growth differentiation factor-9 stimulates proliferation but suppresses the follicle-stimulating
hormone-induced differentiation of cultured granulosa cells from small antral and
preovulatory rat follicles.
Biol Reprod.
2000;
62(2)
370-377
- 19
Buccione R, Vanderhyden B C, Caron P J, Eppig J J.
FSH-induced expansion of the mouse cumulus oophorus in vitro is dependent upon a specific
factor(s) secreted by the oocyte.
Dev Biol.
1990;
138
16-25
- 20
Dragovic R A, Ritter L J, Schulz S J et al..
Oocyte-secreted factor activation of SMAD 2/3 signaling enables initiation of mouse
cumulus cell expansion.
Biol Reprod.
2007;
76(5)
848-857
- 21
Joyce I M, Pendola F L, O'Brien M, Eppig J J.
Regulation of prostaglandin-endoperoxide synthase 2 messenger ribonucleic acid expression
in mouse granulosa cells during ovulation.
Endocrinology.
2001;
142(7)
3187-3197
- 22
Su Y Q, Wigglesworth K, Pendola F L, O'Brien M J, Eppig J J.
Mitogen-activated protein kinase activity in cumulus cells is essential for gonadotropin-induced
oocyte meiotic resumption and cumulus expansion in the mouse.
Endocrinology.
2002;
143(6)
2221-2232
- 23
Su Y Q, Wu X, O'Brien M J et al..
Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus
cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop.
Dev Biol.
2004;
276(1)
64-73
- 24
Vanderhyden B C, Caron P J, Buccione R, Eppig J J.
Developmental pattern of the secretion of cumulus-expansion enabling factor by mouse
oocytes and the role of oocytes in promoting granulosa cell differentiation.
Dev Biol.
1990;
140
307-317
- 25
Eppig J J, Wigglesworth K, Pendola F L.
The mammalian oocyte orchestrates the rate of ovarian follicular development.
Proc Natl Acad Sci U S A.
2002;
99
2890-2894
- 26
Anderson E, Albertini D F.
Gap junctions between the oocyte and companion follicle cells in the mammalian ovary.
J Cell Biol.
1976;
71
680-686
- 27
Albertini D F, Combelles C MH, Benecchi E, Carabatsos M J.
Cellular basis for paracrine regulation of ovarian follicle development.
Reproduction.
2001;
121(5)
647-653
- 28
Ackert C L, Gittens J E, O'Brien M J, Eppig J J, Kidder G M.
Intercellular communication via connexin43 gap junctions is required for ovarian folliculogenesis
in the mouse.
Dev Biol.
2001;
233(2)
258-270
- 29
Juneja S C, Barr K J, Enders G C, Kidder G M.
Defects in the germ line and gonads of mice lacking connexin43.
Biol Reprod.
1999;
60(5)
1263-1270
- 30
Simon A M, Goodenough D A, Li E, Paul D L.
Female infertility in mice lacking connexin 37.
Nature.
1997;
385(6616)
525-529
- 31
Gittens J E, Kidder G M.
Differential contributions of connexin37 and connexin43 to oogenesis revealed in chimeric
reaggregated mouse ovaries.
J Cell Sci.
2005;
118(Pt 21)
5071-5078
- 32
Gershon E, Plaks V, Aharon I et al..
Oocyte-directed depletion of connexin43 using the Cre-LoxP system leads to subfertility
in female mice.
Dev Biol.
2008;
313(1)
1-12
- 33
Li T Y, Colley D, Barr K J, Yee S P, Kidder G M.
Rescue of oogenesis in Cx37-null mutant mice by oocyte-specific replacement with Cx43.
J Cell Sci.
2007;
120(Pt 23)
4117-4125
- 34
Paladino G.
I ponti intercellulari tra l'uovo ovarico e le cellule follicolari e la formazione
della zona pellucida.
Anat Anz.
1890;
15
254-259
- 35
Biggers J D, Whittingham D G, Donahue R P.
The pattern of energy metabolism in the mouse oocyte and zygote.
Proc Natl Acad Sci U S A.
1967;
58
560-567
- 36
Donahue R P, Stern S.
Follicular cell support of oocyte maturation: production of pyruvate in vitro.
J Reprod Fertil.
1968;
17(2)
395-398
- 37
Leese H J, Barton A M.
Production of pyruvate by isolated mouse cumulus cells.
J Exp Zool.
1985;
234(2)
231-236
- 38
Herubel F, El Mouatassim S, Guerin P, Frydman R, Menezo Y.
Genetic expression of monocarboxylate transporters during human and murine oocyte
maturation and early embryonic development.
Zygote.
2002;
10(2)
175-181
- 39
Brinster R L.
Oxidation of pyruvate and glucose by oocytes of the mouse and rhesus monkey.
J Reprod Fertil.
1971;
24(2)
187-191
- 40
Eppig J J.
Analysis of mouse oogenesis in vitro. Oocyte isolation and the utilization of exogenous
energy sources by growing oocytes.
J Exp Zool.
1976;
198
375-386
- 41
Downs S M, Humpherson P G, Leese H J.
Pyruvate utilization by mouse oocytes is influenced by meiotic status and the cumulus
oophorus.
Mol Reprod Dev.
2002;
62(1)
113-123
- 42
Johnson M T, Freeman E A, Gardner D K, Hunt P A.
Oxidative metabolism of pyruvate is required for meiotic maturation of murine oocytes
in vivo.
Biol Reprod.
2007;
77(1)
2-8
- 43
Sugiura K, Pendola F L, Eppig J J.
Oocyte control of metabolic cooperativity between oocytes and companion granulosa
cells: energy metabolism.
Dev Biol.
2005;
279(1)
20-30
- 44
Tsutsumi O, Satoh K, Taketani Y, Kato T.
Determination of enzyme activities of energy metabolism in the maturing rat oocyte.
Mol Reprod Dev.
1992;
33(3)
333-337
- 45
Cetica P, Pintos L, Dalvit G, Beconi M.
Activity of key enzymes involved in glucose and triglyceride catabolism during bovine
oocyte maturation in vitro.
Reproduction.
2002;
124(5)
675-681
- 46
Rieger D, Loskutoff N M.
Changes in the metabolism of glucose, pyruvate, glutamine and glycine during maturation
of cattle oocytes in vitro.
J Reprod Fertil.
1994;
100(1)
257-262
- 47
Rushmer R A, Brinster R L.
Carbon dioxide production from pyruvate and glucose by bovine oocytes.
Exp Cell Res.
1973;
82(2)
252-254
- 48
Tsutsumi O, Yano T, Satoh K, Mizuno M, Kato T.
Studies of hexokinase activity in human and mouse oocyte.
Am J Obstet Gynecol.
1990;
162(5)
1301-1304
- 49
Dworkin M B, Dworkin-Rastl E.
Carbon metabolism in early amphibian embryos.
Trends Biochem Sci.
1991;
16(6)
229-234
- 50
Eppig J J, Steckman M L.
Comparison of exogenous energy sources for in vitro maintenance of follicle cell-free
Xenopus laevis oocytes.
In Vitro.
1976;
12(3)
173-179
- 51
Colonna R, Mangia F.
Mechanisms of amino acid uptake in cumulus-enclosed mouse oocytes.
Biol Reprod.
1983;
28
797-803
- 52
Eppig J J, Pendola F L, Wigglesworth K, Pendola J K.
Mouse oocytes regulate metabolic cooperativity between granulosa cells and oocytes:
amino acid transport.
Biol Reprod.
2005;
73(2)
351-357
- 53
Su Y Q, Sugiura K, Wigglesworth K et al..
Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes:
BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells.
Development.
2008;
135(1)
111-121
- 54
Sato N, Kawamura K, Fukuda J et al..
Expression of LDL receptor and uptake of LDL in mouse preimplantation embryos.
Mol Cell Endocrinol.
2003;
202(1–2)
191-194
- 55
Trigatti B, Rayburn H, Vinals M et al..
Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular
pathophysiology.
Proc Natl Acad Sci U S A.
1999;
96(16)
9322-9327
- 56
Li X, Peegel H, Menon K M.
In situ hybridization of high density lipoprotein (scavenger, type 1) receptor messenger
ribonucleic acid (mRNA) during folliculogenesis and luteinization: evidence for mRNA
expression and induction by human chorionic gonadotropin specifically in cell types
that use cholesterol for steroidogenesis.
Endocrinology.
1998;
139(7)
3043-3049
- 57
Miettinen H E, Rayburn H, Krieger M.
Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor
(SR-BI)-deficient mice.
J Clin Invest.
2001;
108(11)
1717-1722
- 58
Perret B P, Parinaud J, Ribbes H et al..
Lipoprotein and phospholipid distribution in human follicular fluids.
Fertil Steril.
1985;
43(3)
405-409
- 59
Simpson E R, Rochelle D B, Carr B R, MacDonald P C.
Plasma lipoproteins in follicular fluid of human ovaries.
J Clin Endocrinol Metab.
1980;
51(6)
1469-1471
- 60
Ishibashi S, Brown M S, Goldstein J L et al..
Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal
by adenovirus-mediated gene delivery.
J Clin Invest.
1993;
92(2)
883-893
- 61
Sugiura K, Eppig J J.
Control of metabolic cooperativity between oocytes and their companion granulosa cells
by mouse oocytes.
Reprod Fertil Dev.
2005;
17(7)
667-674
- 62
Zuelke K A, Brackett B G.
Effects of luteinizing hormone on glucose metabolism in cumulus-enclosed bovine oocytes
matured in vitro.
Endocrinology.
1992;
131(6)
2690-2696
- 63
Sutton M L, Cetica P D, Beconi M T et al..
Influence of oocyte-secreted factors and culture duration on the metabolic activity
of bovine cumulus cell complexes.
Reproduction.
2003;
126(1)
27-34
- 64
Gilchrist R B, Ritter L J, Armstrong D T.
Oocyte-somatic cell interactions during follicle development in mammals.
Anim Reprod Sci.
2004;
82–83
431-446
- 65
Ralph J H, Telfer E E, Wilmut I.
Bovine cumulus cell expansion does not depend on the presence of an oocyte secreted
factor.
Mol Reprod Dev.
1995;
42(2)
248-253
- 66
Juengel J L, McNatty K P.
The role of proteins of the transforming growth factor-beta superfamily in the intraovarian
regulation of follicular development.
Hum Reprod Update.
2005;
11(2)
143-160
- 67
Dube J L, Wang P, Elvin J et al..
The bone morphogenetic protein 15 gene is X-linked and expressed in oocytes.
Mol Endocrinol.
1998;
12(12)
1809-1817
- 68
McGrath S A, Esquela A F, Lee S J.
Oocyte-specific expression of growth differentiation factor-9.
Mol Endocrinol.
1995;
9(1)
131-136
- 69
McPherron A C, Lee S J.
GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily
containing a novel pattern of cysteines.
J Biol Chem.
1993;
268(5)
3444-3449
- 70
Elvin J A, Yan C N, Wang P, Nishimori K, Matzuk M M.
Molecular characterization of the follicle defects in the growth differentiation factor
9-deficient ovary.
Mol Endocrinol.
1999;
13(6)
1018-1034
- 71
Yan C, Wang P, DeMayo J et al..
Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor
9 in ovarian function.
Mol Endocrinol.
2001;
15(6)
854-866
- 72
Bodin L, Di Pasquale E, Fabre S et al..
A novel mutation in the bone morphogenetic protein 15 gene causing defective protein
secretion is associated with both increased ovulation rate and sterility in Lacaune
sheep.
Endocrinology.
2007;
148(1)
393-400
- 73
Juengel J L, Hudson N L, Heath D A et al..
Growth differentiation factor 9 and bone morphogenetic protein 15 are essential for
ovarian follicular development in sheep.
Biol Reprod.
2002;
67(6)
1777-1789
- 74
Chand A L, Ponnampalam A P, Harris S E, Winship I M, Shelling A N.
Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure.
Fertil Steril.
2006;
86(4)
1009-1012
- 75
Di Pasquale E, Rossetti R, Marozzi A et al..
Identification of new variants of human BMP15 gene in a large cohort of women with
premature ovarian failure.
J Clin Endocrinol Metab.
2006;
91(5)
1976-1979
- 76
Dixit H, Rao L K, Padmalatha V V et al..
Missense mutations in the BMP15 gene are associated with ovarian failure.
Hum Genet.
2006;
119(4)
408-415
- 77
Palmer J S, Zhao Z Z, Hoekstra C et al..
Novel variants in growth differentiation factor 9 in mothers of dizygotic twins.
J Clin Endocrinol Metab.
2006;
91(11)
4713-4716
- 78
Gueripel X, Brun V, Gougeon A.
Oocyte bone morphogenetic protein 15, but not growth differentiation factor 9, is
increased during gonadotropin-induced follicular development in the immature mouse
and is associated with cumulus oophorus expansion.
Biol Reprod.
2006;
75(6)
836-843
- 79
Yoshino O, McMahon H E, Sharma S, Shimasaki S.
A unique preovulatory expression pattern plays a key role in the physiological functions
of BMP-15 in the mouse.
Proc Natl Acad Sci U S A.
2006;
103(28)
10678-10683
- 80
McMahon H E, Hashimoto O, Mellon P L, Shimasaki S.
Oocyte-specific overexpression of mouse BMP-15 leads to accelerated folliculogenesis
and an early onset of acyclicity in transgenic mice.
Endocrinology.
2008;
149(6)
2807-2815
- 81
Sugiura K, Su Y Q, Diaz F J et al..
Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells.
Development.
2007;
134(14)
2593-2603
- 82
Buratini Jr J, Teixeira A B, Costa I B et al..
Expression of fibroblast growth factor-8 and regulation of cognate receptors, fibroblast
growth factor receptor-3c and -4, in bovine antral follicles.
Reproduction.
2005;
130(3)
343-350
- 83
Valve E, Penttila T L, Paranko J, Harkonen P.
FGF-8 is expressed during specific phases of rodent oocyte and spermatogonium development.
Biochem Biophys Res Commun.
1997;
232(1)
173-177
- 84
van Wezel I L, Umapathysivam K, Tilley W D, Rodgers R J.
Immunohistochemical localization of basic fibroblast growth factor in bovine ovarian
follicles.
Mol Cell Endocrinol.
1995;
115(2)
133-140
- 85
Tamura H, Takasaki A, Miwa I et al..
Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical
damage and improves fertilization rate.
J Pineal Res.
2008;
44(3)
280-287
- 86
Ito Y, Kihara M, Nakamura E, Yonezawa S, Yoshizaki N.
Vitellogenin transport and yolk formation in the quail ovary.
Zoolog Sci.
2003;
20(6)
717-726
- 87
Monaco M E, Villecco E I, Sanchez S S.
Implication of gap junction coupling in amphibian vitellogenin uptake.
Zygote.
2007;
15(2)
149-157
- 88
Waksmonski S L, Woodruff R I.
For uptake of yolk precursors, epithelial cell-oocyte gap junctional communication
is required by insects representing six different orders.
J Insect Physiol.
2002;
48(6)
667-675
- 89
Kayampilly P P, Menon K M.
Follicle-stimulating hormone increases tuberin phosphorylation and mammalian target
of rapamycin signaling through an extracellular signal-regulated kinase-dependent
pathway in rat granulosa cells.
Endocrinology.
2007;
148(8)
3950-3957
- 90
Yaba A, Bianchi V, Borini A, Johnson J.
A putative mitotic checkpoint dependent on mTOR function controls cell proliferation
and survival in ovarian granulosa cells.
Reprod Sci.
2008;
15(2)
128-138
- 91
Alam H, Maizels E T, Park Y et al..
Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol
3-kinase/AKT/Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR)
pathway is necessary for induction of select protein markers of follicular differentiation.
J Biol Chem.
2004;
279(19)
19431-19440
- 92
Chen Y J, Hsiao P W, Lee M T et al..
Interplay of PI3K and cAMP/PKA signaling, and rapamycin-hypersensitivity in TGFbeta1
enhancement of FSH-stimulated steroidogenesis in rat ovarian granulosa cells.
J Endocrinol.
2007;
192(2)
405-419
- 93
Hunzicker-Dunn M, Maizels E T.
FSH signaling pathways in immature granulosa cells that regulate target gene expression:
branching out from protein kinase A.
Cell Signal.
2006;
18(9)
1351-1359
- 94
Hussein T S, Froiland D A, Amato F, Thompson J G, Gilchrist R B.
Oocytes prevent cumulus cell apoptosis by maintaining a morphogenic paracrine gradient
of bone morphogenetic proteins.
J Cell Sci.
2005;
118(Pt 22)
5257-5268
- 95
Rung E, Friberg P A, Bergh C, Billig H.
Depletion of substrates for protein prenylation increases apoptosis in human periovulatory
granulosa cells.
Mol Reprod Dev.
2006;
73(10)
1277-1283
- 96
Rung E, Friberg P A, Shao R et al..
Progesterone-receptor antagonists and statins decrease de novo cholesterol synthesis
and increase apoptosis in rat and human periovulatory granulosa cells in vitro.
Biol Reprod.
2005;
72(3)
538-545
- 97
Johnson J, Espinoza T, McGaughey R W, Rawls A, Wilson-Rawls J.
Notch pathway genes are expressed in mammalian ovarian follicles.
Mech Dev.
2001;
109(2)
355-361
- 98
Pan H, O'Brien M J, Wigglesworth K, Eppig J J, Schultz R M.
Transcript profiling during mouse oocyte development and the effect of gonadotropin
priming and development in vitro.
Dev Biol.
2005;
286(2)
493-506
- 99
Russell M C, Cowan R G, Harman R M, Walker A L, Quirk S M.
The hedgehog signaling pathway in the mouse ovary.
Biol Reprod.
2007;
77(2)
226-236
You-Qiang SuPh.D.
The Jackson Laboratory
600 Main Street, Bar Harbor, ME 04609
eMail: youqiang.su@jax.org
