CHAPTER 7 Growth Factors and Reproduction 140.

e1

Table S7.1 Phenotypes for Mice with Mutations in PGC Pathway Components (Ordered Based on Temporal
Function During Embryogenesis)
Gene Symbol Phenotype; Findings References
Bmp2 Embryonic lethal; reduced PGC 1,2

Bmp4 Embryonic lethal; no PGC 3,4

Bmp8b Viable; male infertility; reduced PGC 5,6

Smad1 Embryonic lethal; reduced PGC 7-9

Smad5 Embryonic lethal; reduced PGC 10-12

Smad4 Embryonic lethal; absent PGC 13-15

Prdm1 (Blimp1) Embryonic lethal; PGC specification defect 16

Prdm14 Infertility; PGC specification defect 17

Pou5f1 (Oct4) Pluripotency marker 18,19

Nanog Pluripotency marker 19-21

Sox2 Pluripotency marker 19,22

Kitl Variable phenotypes depending on mutation; PGC migration defect 23

Kit Variable phenotypes depending on mutation; PGC migration defect 23

Tgfbr1 (ALK5) Embryonic lethal; enhanced PGC migration 24,25

Table S7.2 Mouse Models for Ligands in the TGFB Family

Mutant Gene Reproductive Phenotype Fertility Status References
Amh Increased primordial follicle activation Normal 26

Bmp6 Reduced ovulation Subfertile 27

Bmp7 Reduced primordial germ cells N.A. 28

Bmp15 Decreased ovulation and fertilization rates Normal to subfertile 29

Gdf9 Follicular arrest at the primary follicle stage Infertile 30

Fst Loss of oocytes by birth N.A. 31

Fst (Conditional) Reduced growing follicles, ovulation and fertilization defects Subfertile to infertile 32

Inha (Conditional) Increased polyovular follicles Subfertile 33

Inhbb Lactation defects Infertile 34

Inhba Inhbb (Conditional) Increased numbers of antral follicles and accumulation of corpora Infertile 33

lutea
Tgfb2 Increased oocytes at birth N.A.* 35

*N.A., Not available due to embryonic or perinatal lethality.

Table S7.3 Phenotypes of Mice with Ovarian Deletion of the SMAD Transcription Factors
Gene Cre Cell-Specific Deletion Reproductive Phenotype Fertility Status References
Smad1 Amhr2cre Granulosa cell None Normal 36

Smad2 Amhr2cre Granulosa cell None Normal 37

Smad3 Amhr2cre Granulosa cell None Normal 37

Smad4 Amhr2cre Granulosa cell Reduced antral follicles and ­ovulation Subfertile, then 50% 38

rates, cumulus cell defects, increased infertile by 6 months

luteinization, increased progesterone
Smad4 Gdf9-icre Oocyte Reduced litter sizes Subfertile 39

Smad4 Zp3-cre Oocyte Normal

Smad5 Amhr2cre Granulosa cell None Normal 36

Smad8 Knockout Global None Normal 36

Smad2 Smad3 Amhr2cre Granulosa cell Reduced antral follicles and ­ovulation Subfertile, then infertile 37
rates, cumulus cell defects at 5 months
Smad1 Smad8 Amhr2cre Granulosa cell None Normal Unpublished
data, S. Pangas
Smad5 Smad Amhr2cre Granulosa cell None Normal 36

Smad1 Smad5 Amhr2cre Granulosa cell Granulosa cell tumors Subfertile, then infertile 36
at 4-6 months
Smad1 Smad5 Amhr2cre Granulosa cell Granulosa cell tumors Subfertile, then infertile 36
Smad8 at 4-6 months
140.e2 PART 1 Endocrinology of Reproduction

Table S7.4 Mutations Affecting Ovulation Rate and Prolificacy Sheep BMP15 and GDF9
Gene Mutation Breeds Protein Domain Mutation Type References
GDF9 FecGH Belclare, Cambridge Mature Substitution 40

FecGE Santa Inês* Mature Substitution 41

BMP15 FecXB Belclare Mature Substitution 40

FecXI Inverdale Mature Substitution 42

FecXH Hanna Mature Premature stop 42

FecXG Galway Prepro Substitution; premature stop 40

FecXL Lacaune Mature Substitution 43

FecXR Rasa Aragonesa Premature stop 44

BMPR1B FecB Booroola†, Merlino, Hu, Han, Garole, Kinase domain Substitution 45

Javenese Thin-tail

*Heterozygotes have normal ovulation rates, but rates increase in homozygous sheep.
†Heterozygotes and homozygotes have increased ovulation rates with the heterozygotes midway between homozygotes and non-carriers.

Table S7.5 Mouse Models with Defects in the Periovulatory Period

Mutant Gene Reproductive Phenotype Fertility Status References
Luteinizing hormone b (Lhb) Block in folliculogenesis; early antral stage Infertile 46

Luteinizing hormone/choriogonadotropin Block in folliculogenesis; early antral stage Infertile 47,48

receptor (Lhcgr)
Prostaglandin-endoperoxide synthase 2 Defects in ovulation, cumulus expansion, and implantation Mostly infertile 49,50

(Ptgs2)
Prostaglandin E receptor 2, subtype EP2 Defects in cumulus expansion; decreased fertilization Subfertile 51-53

(Ptger2)
Pentraxin 3 (Ptx3) Defects in cumulus-oocyte complex integrity and ovulation Subfertile 54,55

Tumor necrosis factor alpha induced Impaired cumulus matrix formation resulting in failed Infertile 56

protein 6 (Tnfaip6) cumulus-oocyte complex expansion

CCAAT/enhancer-binding protein b Reduced ovulation; fail to form corpus luteum Infertile 57

(Cebpb)
Nuclear receptor interacting protein Ovulation defect; ovaries accumulate luteinized and Infertile 58

(Nrip1; RIP40) ­unruptured follicles

Progesterone receptor (Pgr; PR) Anovulation; corpora lutea absent Infertile 59

Alpha 1 microglobulin/bikunin (Ambp) Defects in ovulation and cumulus-oocyte complex integrity Subfertile 60,61

Amphiregulin (Areg) Suppressed cumulus expansion, delayed meiotic reentry Subfertile 62

Bone morphogenetic protein 15 (Bmp15) Defects in cumulus expansion and ovulation Subfertile 29

Bone morphogenetic protein receptor, Defects in estrous cyclicity, cumulus expansion, and Subfertile 63

type IB (Bmpr1b) ­endometrial gland development

Epiregulin (Eregwa2/wa2; hypomorph) Suppressed cumulus expansion, defective meiotic Subfertile 62

­resumption, ovulation defect

MAD homolog 4 (Smad4) Premature luteinization; decreased ovulation with trapped Subfertile 38

(cKO) oocytes

Table S7.6 Main Genes Involved in the Development of the Reproductive Tracts
Gene Phenotype References
Pax2 Null mice show neonatal lethality; males and females lack kidneys, ureters, and genital tracts 64

Emx2 Null mice show neonatal lethality; females and males lack kidneys, ureters, gonads, and genital tracts 65

Lim1 Null mice show embryonic lethality; females lack müllerian duct 66
 CHAPTER 7 Growth Factors and Reproduction 140.e3

Table S7.7 Genes Involved in Müllerian Duct Regression and Development

Gene Phenotype References
Amh Null males have a complete male reproductive tract and functional sperm, but also uterus and oviducts; 67,68

females are fertile with enlarged ovaries. Female mice overexpressing Amh show blind vagina and no uterus
or oviducts
Amhr2 Null males have a normal male reproductive tract, but also uterus and oviducts 69,70

Alk2, Alk3 Alk2 and Alk3 null mice show embryonic lethality; conditional ablation of Alk2 and Alk3 in the müllerian duct 71,72

mesenchyme (Alk2/Alk3 double conditional knockout mice) causes duct retention in males
Smad1, Smad1 and Smad5 null mice show embryonic lethality; Smad8 null mice are viable and fertile. Deletion of 71

Smad5, Smad5, Smad1/Smad5 or Smad5/Smad8 in the müllerian duct mesenchyme causes partial müllerian duct
Smad8 retention. Smad1/Smad5/Smad8 triple conditional knockout mice show complete müllerian duct retention
Wnt7a Null mice show partial perinatal lethality; null males fail to undergo Mullerian duct regression. Females are 73,74

infertile due to abnormal development of uterus and oviduct

Wnt4 Null mice show neonatal lethality; null females are masculinized: they have Wolffian duct and lack müllerian 75,76

duct
Wnt5a Null mice show perinatal lethality; females show caudal truncation of the reproductive tract and defective 77,78

uterine glandular development

Ctnnb1 Null mice show embryonic lethality; male mice with a conditional deletion of Ctnnb1 in the müllerian duct 79

mesenchyme show müllerian duct retention

Table S7.8 Genes Involved in the Regulation of Embryo Implantation

Gene Phenotype References
Ihh Null mice die before or immediately after birth. Females with a conditional deletion of Ihh in the uterus show 80,81

failure of blastocyst attachment. Decidualization is defective

NR2F2 Null mice show embryonic lethality. Females with a conditional deletion of COUP-TFII in the uterus are sterile; 82

both embryo attachment and uterine decidualization are impaired

Bmp2 Null mice show embryonic lethality; females with a conditional deletion of Bmp2 in the uterus are sterile due to 83

failure of uterine stromal cell decidualization

Wnt4 Null mice show neonatal lethality; female mice with a conditional deletion of Wnt4 in the uterus are severely 84

subfertile due to impaired implantation

Table S7.9 Factors Produced at the Maternal-Fetal Interface; Their Effects on the Invasion, Proliferation, and
Migration of the Trophoblast; and the Intracellular Molecular Pathways That They Regulate
Downstream
Factor Expression Invasion Proliferation Migration Pathway(S) References
EGF Placenta, decidua ↑ ↑ ↑ MAPK, PI3K 85-87

CSF1 Trophoblast, pla- ↔ ↑ n.d. MAPK, JAK/STAT 88-90

centa, decidua
IGFII Trophoblast ↑ ↔ ↑ Gi, MAPK 91-93

IGFBPI Decidua ↑ ↔ ↑ FAK, MAPK 92-94

HGF Placenta ↑ n.d. ↑ PI3K, MAPK, iNOS 95-97

IL11 Decidua, placen- ↑ ↔ ↑ JAK/STAT 98-100

ta, trophoblast
LIF Decidua, placenta ↑ ↑ n.d. JAK/STAT 101-103

TGFβ Decidua, tropho- ↓ ↓ ↓ SMAD2/3 93,104,105

blast
NODAL Placenta, tropho- ↓ ↓ ↓ SMAD2/3 106,107

blast
DECORIN Decidua ↓ ↓ ↓ - 108

n.d., not determined.

140.e4 Supplemental Table References
Supplemental Table References
The following references are cited in the tables.
1. Ying Y, Zhao GQ: Cooperation of endoderm-derived BMP2 and
extraembryonic ectoderm-derived BMP4 in primordial germ cell gen-
eration in the mouse, Dev Biol 232(2):484–492, 2001.
2. Zhang H, Bradley A: Mice deficient for BMP2 are nonviable and have
defects in amnion/chorion and cardiac development, Development
122(10):2977–2986, 1996.
3. Winnier G, et al: Bone morphogenetic protein-4 is required for meso-
derm formation and patterning in the mouse, Genes Dev 9(17):2105–
2116, 1995.
4. Lawson KA, et al: Bmp4 is required for the generation of primordial
germ cells in the mouse embryo, Genes Dev 13(4):424–436, 1999.
5. Zhao G-Q, et al: The gene encoding bone morphogenetic protein 8B is
required for the initiation and maintenance of spermatogenesis in the
mouse, Genes Dev 10:1657–1669, 1996.
6. Ying Y, et al: Requirement of BMP8b for the generation of primordial
germ cells in the mouse, Mol Endocrinol 14(7):1053–1063, 2000.
7. Tremblay KD, Dunn NR, Robertson EJ: Mouse embryos lacking
Smad1 signals display defects in extra-embryonic tissues and germ cell
formation, Development 128(18):3609–3621, 2001.
8. Lechleider RJ, et al: Targeted mutagenesis of Smad1 reveals an essen-
tial role in chorioallantoic fusion, Dev Biol 240(1):157–167, 2001.
9. Hayashi K, et al: SMAD1 signaling is critical for initial commitment of
germ cell lineage from mouse epiblast, Mech Dev 118(1-2):99–109, 2002.
10. Chang H, et al: Smad5 knockout mice die at mid-gestation due to
multiple embryonic and extraembryonic defects, Development
126:1631–1642, 1999.
11. Yang X, et al: Angiogenesis defects and mesenchymal apoptosis in
mice lacking SMAD5, Development 126(8):1571–1580, 1999.
12. Chang H, Matzuk MM: Smad5 is required for mouse primordial germ
cell development, Mech Dev 104(1-2):61–67, 2001.
13. Sirard C, et al: The tumor suppressor gene Smad4/Dpc4 is required
for gastrulation and later for anterior development of the mouse
embryo, Genes Dev 12(1):107–119, 1998.
14. Yang X, et al: The tumor suppressor SMAD4/DPC4 is essential for
epiblast proliferation and mesoderm induction in mice, Proc Natl
Acad Sci U S A 95(7):3667–3672, 1998.
15. Chu GC, et al: Differential requirements for Smad4 in TGFbeta-
dependent patterning of the early mouse embryo, Development
131(15):3501–3512, 2004.
16. Ohinata Y, et al: Blimp1 is a critical determinant of the germ cell
lineage in mice, Nature 436(7048):207–213, 2005.
17. Yamaji M, et al: Critical function of Prdm14 for the establishment of
the germ cell lineage in mice, Nat Genet 40(8):1016–1022, 2008.
18. Scholer HR, et al: A family of octamer-specific proteins present during
mouse embryogenesis: evidence for germline-specific expression of an
Oct factor, EMBO J 8(9):2543–2550, 1989.
19. Boyer LA, et al: Core transcriptional regulatory circuitry in human
embryonic stem cells, Cell 122(6):947–956, 2005.
20. Chambers I, et al: Functional expression cloning of Nanog, a pluripotency
sustaining factor in embryonic stem cells, Cell 113(5):643–655, 2003.
21. Mitsui K, et al: The homeoprotein Nanog is required for maintenance of
pluripotency in mouse epiblast and ES cells, Cell 113(5):631–642, 2003.
22. Botquin V, et al: New POU dimer configuration mediates antagonistic
control of an osteopontin preimplantation enhancer by Oct-4 and Sox-
2, Genes Dev 12(13):2073–2090, 1998.
23. Donovan P, de Miguel MP: The role of C-Kit/Kit ligand axis in mam-
malian gametogenesis. In Matzuk MM, Brown CW, Kumar TR, editors:
Transgenics in endocrinology, 2001, The Humana Press, pp 147–163.
24. Larsson J, et al: Abnormal angiogenesis but intact hematopoi-
etic potential in TGF-beta type I receptor-deficient mice, Embo J
20(7):1663–1673, 2001.
25. Chuva de Sousa Lopes SM, et al: Altered primordial germ cell migra-
tion in the absence of transforming growth factor beta signaling via
ALK5, Dev Biol 284(1):194–203, 2005.
26. Durlinger AL, et al: Anti-Mullerian hormone inhibits initiation
of primordial follicle growth in the mouse ovary, Endocrinology
143(3):1076–1084, 2002.
27. Sugiura K, Su YQ, Eppig JJ: Does bone morphogenetic protein 6
(BMP6) affect female fertility in the mouse? Biol Reprod 83(6):997–
1004, 2010.
28. Zhao GQ, et al: Mutation in Bmp7 exacerbates the phenotype
of Bmp8a mutants in spermatogenesis and epididymis, Dev Biol
240(1):212–222, 2001.
29. Yan C, et al: Synergistic roles of bone morphogenetic protein 15 and
growth differentiation factor 9 in ovarian function, Mol Endocrinol
15(6):854–866, 2001.
30. Dong J, et al: Growth differentiation factor-9 is required during early
ovarian folliculogenesis, Nature 383(6600):531–535, 1996.
31. Matzuk MM, et al: Multiple defects and perinatally death in mice
deficient in follistatin, Nature 372:360–363, 1995.
32. Jorgez CJ, et al: Granulosa cell-specific inactivation of follistatin
causes female fertility defects, Mol Endocrinol 18(4):953–967, 2004.
33. Pangas SA, et al: Intraovarian activins are required for female fertility,
Mol Endocrinol 21(10):2458–2471, 2007.
34. Vassalli A, et al: Activin/inhibin βB subunit gene disruption leads to
defects in eyelid development and female reproduction, Genes Dev
8(4):414–427, 1994.
35. Memon MA, et al: Transforming growth factor beta (TGFbeta1, TGF-
beta2 and TGFbeta3) null-mutant phenotypes in embryonic gonadal
development, Mol Cell Endocrinol 294(1-2):70–80, 2008.
36. Pangas SA, et al: Conditional deletion of Smad1 and Smad5 in somatic
cells of male and female gonads leads to metastatic tumor develop-
ment in mice, Mol Cell Biol 28(1):248–257, 2008.
37. Verpoest W, et al: Real and expected delivery rates of patients with myo-
tonic dystrophy undergoing intracytoplasmic sperm injection and preim-
plantation genetic diagnosis, Hum Reprod 23(7):1654–1660, 2008.
38. Pangas SA, et al: Premature luteinization and cumulus cell defects in
ovarian-specific Smad4 knockout mice, Mol Endocrinol 20(6):1406–
1422, 2006.
39. Li X, et al: Minimal fertility defects in mice deficient in oocyte-
expressed Smad4, Biol Reprod 86(1):1–6, 2012.
40. Hanrahan JP, et al: Mutations in the genes for oocyte-derived growth
factors GDF9 and BMP15 are associated with both increased ovula-
tion rate and sterility in Cambridge and Belclare sheep (Ovis aries),
Biol Reprod 70(4):900–909, 2004.
41. Silva BD, et al: A new polymorphism in the Growth and Differentia-
tion Factor 9 (GDF9) gene is associated with increased ovulation rate
and prolificacy in homozygous sheep, Anim Genet 42(1):89–92, 2011.
42. Galloway SM, et al: Mutations in an oocyte-derived growth factor
gene (BMP15) cause increased ovulation rate and infertility in a dos-
age-sensitive manner, Nat Genet 25(3):279–283, 2000.
43. Bodin L, 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
148(1):393–400, 2007.
44. Martinez-Royo A, et al: A deletion in the bone morphogenetic protein
15 gene causes sterility and increased prolificacy in Rasa Aragonesa
sheep, Anim Genet 39(3):294–297, 2008.
45. Wilson T, et al: Highly prolific Booroola sheep have a mutation in the
intracellular kinase domain of bone morphogenetic protein IB recep-
tor (ALK-6) that is expressed in both oocytes and granulosa cells, Biol
Reprod 64(4):1225–1235, 2001.
46. Ma X, et al: Targeted disruption of luteinizing hormone β subunit leads
to hypogonadism, defects in gonadal steroidogenesis and infertility,
Proc Natl Acad Sci USA 101(49):17294–17299, 2004.
47. Lei ZM, et al: Targeted disruption of luteinizing hormone/human chori-
onic gonadotropin receptor gene, Mol Endocrinol 15(1):184–200, 2001.
48. Zhang FP, et al: Normal prenatal but arrested postnatal sexual devel-
opment of luteinizing hormone receptor knockout (LuRKO) mice,
Mol Endocrinol 15(1):172–183, 2001.
49. Dinchuk JE, et al: Renal abnormalities and an altered inflammatory
response in mice lacking cyclooxygenase II, Nature 378:406–409, 1995.
50. Lim H, et al: Multiple female reproductive failures in cyclooxygenase
2-deficient mice, Cell 91:197–208, 1997.
51. Hizaki H, et al: Abortive expansion of the cumulus and impaired fer-
tility in mice lacking the prostaglandin E receptor subtype EP(2), Proc
Natl Acad Sci USA 96(18):10501–10506, 1999.
52. Kennedy CRJ, et al: Salt-sensitive hypertension and reduced fertil-
ity in mice lacking the prostaglandin EP2 receptor, Nature Medicine
5(2):217–220, 1999.
53. Tilley SL, et al: Reproductive failure and reduced blood pressure in
mice lacking the EP2 prostaglandin E2 receptor, The Journal of Clini-
cal Investigation 103(11):1539–1545, 1999.
54. Salustri A, et al: PTX3 plays a key role in the organization of the
cumulus oophorus extracellular matrix and in in vivo fertilization,
Development 131(7):1577–1586, 2004.
55. Varani S, et al: Knockout of pentraxin 3, a downstream target of
growth differentiation factor-9, causes female subfertility, Molecular
Endocrinology 16:1154–1167, 2002.

56. Fulop C, et al: Impaired cumulus mucification and female sterility in
tumor necrosis factor-induced protein-6 deficient mice, Development
130(10):2253–2261, 2003.
57. Sterneck E, Tessarollo L, Johnson PF: An essential role for C/EBPβ in
female reproduction, Genes & Development 11:2153–2162, 1997.
58. White R, et al: The nuclear receptor co-repressor nrip1 (RIP140) is
essential for female fertility, Nat Med 6(12):1368–1374, 2000.
59. Lydon JP, et al: Mice lacking progesterone receptor exhibit pleiotro-
pic reproductive abnormalities, Genes and Development 9:2266–2278,
1995.
60. Sato H, et al: Impaired fertility in female mice lacking urinary trypsin
inhibitor, Biochem Biophys Res Commun 281(5):1154–1160, 2001.
61. Zhuo L, et al: Defect in SHAP-hyaluronan complex causes severe
female infertility. A study by inactivation of the bikunin gene in mice,
J Biol Chem 276(11):7693–7696, 2001.
62. Hsieh M, et al: Luteinizing hormone-dependent activation of the epi-
dermal growth factor network is essential for ovulation, Mol Cell Biol
27(5):1914–1924, 2007.
63. Yi SE, et al: The type I BMP receptor BmprIB is essential for female
reproductive function, Proc Natl Acad Sci U S A 98(14):7994–7999,
2001.
64. Torres M, et al: Pax-2 controls multiple steps of urogenital develop-
ment, Development 121(12):4057–4065, 1995.
65. Miyamoto N, et al: Defects of urogenital development in mice lacking
Emx2, Development 124(9):1653–1664, 1997.
66. Kobayashi A, et al: Requirement of Lim1 for female reproductive tract
development, Development 131(3):539–549, 2004.
67. Behringer RR, Finegold MJ, Cate RL: Mullerian-inhibiting substance
function during mammalian sexual development, Cell 79(3):415–425,
1994.
68. Behringer RR, et al: Abnormal sexual development in transgenic
mice chronically expressing mullerian inhibiting substance, Nature
345(6271):167–170, 1990.
69. Mishina Y, et al: Genetic analysis of the Mullerian-inhibiting sub-
stance signal transduction pathway in mammalian sexual differentia-
tion, Genes Dev 10(20):2577–2587, 1996.
70. Mishina Y, et al: High specificity of Mullerian-inhibiting substance sig-
naling in vivo, Endocrinology 140(5):2084–2088, 1999.
71. Orvis GD, et al: Functional redundancy of TGF-beta family type
I receptors and receptor-Smads in mediating anti-Mullerian hor-
mone-induced Mullerian duct regression in the mouse, Biol Reprod
78(6):994–1001, 2008.
72. Jamin SP, et al: Requirement of Bmpr1a for Mullerian duct regression
during male sexual development, Nat Genet 32(3):408–410, 2002.
73. Parr BA, McMahon AP: Sexually dimorphic development of the mam-
malian reproductive tract requires Wnt-7a, Nature 395(6703):707–
710, 1998.
74. Miller C, Sassoon DA: Wnt-7a maintains appropriate uterine pattern-
ing during the development of the mouse female reproductive tract,
Development 125(16):3201–3211, 1998.
75. Vainio S, et al: Female development in mammals is regulated by Wnt-4
signalling, Nature 397(6718):405–409, 1999.
76. Stark K, et al: Epithelial transformation of metanephric mesenchyme
in the developing kidney regulated by Wnt-4, Nature 372(6507):679–
683, 1994.
77. Mericskay M, Kitajewski J, Sassoon D: Wnt5a is required for proper
epithelial-mesenchymal interactions in the uterus, Development
131(9):2061–2072, 2004.
78. Yamaguchi TP, et al: A Wnt5a pathway underlies outgrowth of mul-
tiple structures in the vertebrate embryo, Development 126(6):1211–
1223, 1999.
79. Kobayashi A, et al: beta-Catenin is essential for Mullerian duct regres-
sion during male sexual differentiation, Development 138(10):1967–
1975, 2011.
80. Lee K, et al: Indian hedgehog is a major mediator of progesterone
signaling in the mouse uterus, Nat Genet 38(10):1204–1209, 2006.
81. Takamoto N, et al: Identification of Indian hedgehog as a progesterone-
responsive gene in the murine uterus, Mol Endocrinol 16(10):2338–
2348, 2002.
82. Kurihara I, et al: COUP-TFII mediates progesterone regulation of uter-
ine implantation by controlling ER activity, PLoS Genet 3(6):e102, 2007.
83. Lee KY, et al: Bmp2 is critical for the murine uterine decidual
response, Mol Cell Biol 27(15):5468–5478, 2007.
84. Franco HL, et al: WNT4 is a key regulator of normal postnatal uterine
development and progesterone signaling during embryo implantation
and decidualization in the mouse, FASEB J 25(4):1176–1187, 2011.
Supplemental Table References 140.e5
85. Qiu Q, et al: EGF-induced trophoblast secretion of MMP-9 and
TIMP-1 involves activation of both PI3K and MAPK signalling path-
ways, Reproduction 128(3):355–363, 2004.
86. Bass KE, et al: Human cytotrophoblast invasion is up-regulated by
epidermal growth factor: evidence that paracrine factors modify this
process, Dev Biol 164(2):550–561, 1994.
87. Threadgill DW, et al: Targeted disruption of mouse EGF recep-
tor: effect of genetic background on mutant phenotype, Science
269(5221):230–234, 1995.
88. Rajaraman G, et al: Homeobox gene HLX1 is a regulator of colony
stimulating factor-1 dependent trophoblast cell proliferation, Placenta
28(10):991–998, 2007.
89. Marino VJ, Roguin LP: The granulocyte colony stimulating factor
(G-CSF) activates Jak/STAT and MAPK pathways in a trophoblastic
cell line, J Cell Biochem 103(5):1512–1523, 2008.
90. Hamilton GS, et al: Effects of colony stimulating factor-1 on human
extravillous trophoblast growth and invasion, J Endocrinol 159(1):69–
77, 1998.
91. McKinnon T, et al: Stimulation of human extravillous trophoblast
migration by IGF-II is mediated by IGF type 2 receptor involving
inhibitory G protein(s) and phosphorylation of MAPK, J Clin Endo-
crinol Metab 86(8):3665–3674, 2001.
92. Hamilton GS, et al: Autocrine-paracrine regulation of human tropho-
blast invasiveness by insulin-like growth factor (IGF)-II and IGF-bind-
ing protein (IGFBP)-1, Exp Cell Res 244(1):147–156, 1998.
93. Irving JA, Lala PK: Functional role of cell surface integrins on human
trophoblast cell migration: regulation by TGF-beta, IGF-II, and
IGFBP-1, Exp Cell Res 217(2):419–427, 1995.
94. Gleeson LM, et al: Insulin-like growth factor-binding protein 1 stimu-
lates human trophoblast migration by signaling through alpha 5 beta 1
integrin via mitogen-activated protein Kinase pathway, J Clin Endocri-
nol Metab 86(6):2484–2493, 2001.
95. Cartwright JE, Tse WK, Whitley GS: Hepatocyte growth factor
induced human trophoblast motility involves phosphatidylinositol-3-
kinase, mitogen-activated protein kinase, and inducible nitric oxide
synthase, Exp Cell Res 279(2):219–226, 2002.
96. Kauma SW, Bae-Jump V, Walsh SW: Hepatocyte growth factor stimu-
lates trophoblast invasion: a potential mechanism for abnormal placenta-
tion in preeclampsia, J Clin Endocrinol Metab 84(11):4092–4096, 1999.
97. Schmidt C, et al: Scatter factor/hepatocyte growth factor is essential
for liver development, Nature 373(6516):699–702, 1995.
98. Paiva P, et al: Interleukin-11 promotes migration, but not prolifera-
tion, of human trophoblast cells, implying a role in placentation, Endo-
crinology 148(11):5566–5572, 2007.
99. Suman P, et al: Interleukin-11 increases invasiveness of JEG-3 chorio-
carcinoma cells by modulating STAT3 expression, J Reprod Immunol
82(1):1–11, 2009.
100. Bilinski P, Roopenian D, Gossler A: Maternal IL-11Ralpha function is
required for normal decidua and fetoplacental development in mice,
Genes Dev 12(14):2234–2243, 1998.
101. Fitzgerald JS, et al: Leukemia inhibitory factor triggers activation of
signal transducer and activator of transcription 3, proliferation, inva-
siveness, and altered protease expression in choriocarcinoma cells, Int
J Biochem Cell Biol 37(11):2284–2296, 2005.
102. Tapia A, et al: Leukemia inhibitory factor promotes human first tri-
mester extravillous trophoblast adhesion to extracellular matrix and
secretion of tissue inhibitor of metalloproteinases-1 and -2, Hum
Reprod 23(8):1724–1732, 2008.
103. Takahashi Y, et al: SOCS3: an essential regulator of LIF receptor sig-
naling in trophoblast giant cell differentiation, EMBO J 22(3):372–
384, 2003.
104. Graham CH, et al: Resistance of malignant trophoblast cells to both
the anti-proliferative and anti-invasive effects of transforming growth
factor-beta, Exp Cell Res 214(1):93–99, 1994.
105. Lash GE, et al: Inhibition of trophoblast cell invasion by TGFB1, 2,
and 3 is associated with a decrease in active proteases, Biol Reprod
73(2):374–381, 2005.
106. Nadeem L, et al: Nodal signals through activin receptor-like kinase 7
to inhibit trophoblast migration and invasion: implication in the pathogen-
esis of preeclampsia, Am J Pathol 178(3):1177–1189, 2011.
107. Munir S, et al: Nodal and ALK7 inhibit proliferation and induce apop-
tosis in human trophoblast cells, J Biol Chem 279(30):31277–31286,
2004.
108. Xu G, et al: Control of proliferation, migration, and invasiveness of
human extravillous trophoblast by decorin, a decidual product, Biol
Reprod 67(2):681–689, 2002.
140.e6 REFERENCES
References
1. Edson MA, Nagaraja AK, Matzuk MM: The mammalian ovary from
genesis to revelation, Endocr Rev 30(6):624–712, 2009.
2. Chang H, Brown CW, Matzuk MM: Genetic analysis of the mamma-
lian TGF-β superfamily, Endocrine Reviews 23:787–823, 2002.
3. Hayashi K, de Sousa Lopes SM, Surani MA: Germ cell specification in
mice, Science 316(5823):394–396, 2007.
4. Saga Y: Mouse germ cell development during embryogenesis, Curr
Opin Genet Dev 18(4):337–341, 2008.
5. Ohinata Y, et al: Blimp1 is a critical determinant of the germ cell
lineage in mice, Nature 436(7048):207–213, 2005.
6. Seki Y, et al: Cellular dynamics associated with the genome-wide
epigenetic reprogramming in migrating primordial germ cells in mice,
Development 134(14):2627–2638, 2007.
7. Chuva de Sousa Lopes SM, et al: Altered primordial germ cell migra-
tion in the absence of transforming growth factor beta signaling via
ALK5, Dev Biol 284(1):194–203, 2005.
8. Farini D, et al: Chemoattractant action and molecular signaling
pathways of Kit ligand on mouse primordial germ cells, Dev Biol
306(2):572–583, 2007.
9. Dudley BM, et al: BMP signaling regulates PGC numbers and motility
in organ culture, Mech Dev 124(1):68–77, 2007.
10. Ross A, Munger S, Capel B: Bmp7 regulates germ cell proliferation in
mouse fetal gonads, Sex Dev 1(2):127–137, 2007.
11. Childs AJ, et al: BMP signaling in the human fetal ovary is develop-
mentally regulated and promotes primordial germ cell apoptosis, Stem
Cells 28(8):1368–1378, 2010.
12. Martins da Silva SJ, et al: Expression of activin subunits and recep-
tors in the developing human ovary: activin A promotes germ cell sur-
vival and proliferation before primordial follicle formation, Dev Biol
266(2):334–345, 2004.
13. van Amerongen R, Nusse R: Towards an integrated view of Wnt signal-
ing in development, Development 136(19):3205–3214, 2009.
14. Yao HH, Aardema J, Holthusen K: Sexually dimorphic regulation of
inhibin beta B in establishing gonadal vasculature in mice, Biol Reprod
74(5):978–983, 2006.
15. Liu CF, Liu C, Yao HH: Building pathways for ovary organogenesis in
the mouse embryo, Curr Top Dev Biol 90:263–290, 2010.
16. Liu CF, Parker K, Yao HH: WNT4/beta-catenin pathway maintains
female germ cell survival by inhibiting activin betaB in the mouse fetal
ovary, PLoS One 5(4):e10382, 2010.
17. Suzuki A, Saga Y: Nanos2 suppresses meiosis and promotes male germ
cell differentiation, Genes Dev 22(4):430–435, 2008.
18. Souquet B, et al: Nodal signaling regulates the entry into meiosis in
fetal germ cells, Endocrinology 153(5):2466–2473, 2012.
19. Mork L, et al: Mouse germ cell clusters form by aggregation as well as
clonal divisions, Mech Dev 128(11-12):591–596, 2012.
20. Pepling ME, Spradling AC: Female mouse germ cells form synchro-
nously dividing cysts, Development 125(17):3323–3328, 1998.
21. Pepling ME: From primordial germ cell to primordial follicle: mamma-
lian female germ cell development, Genesis 44(12):622–632, 2006.
22. Pepling ME: Follicular assembly: mechanisms of action, Reproduction
143(2):139–149, 2012.
23. Iguchi T, et al: Polyovular follicles in mouse ovaries exposed neonatally
to diethylstilbestrol in vivo and in vitro, Biol Reprod 43(3):478–484,
1990.
24. Bristol-Gould SK, et al: Postnatal regulation of germ cells by activin:
the establishment of the initial follicle pool, Dev Biol 298(1):132–148,
2006.
25. Kipp JL, et al: Neonatal exposure to estrogens suppresses activin
expression and signaling in the mouse ovary, Endocrinology
148(5):1968–1976, 2007.
26. Mork L, et al: Temporal differences in granulosa cell specifica-
tion in the ovary reflect distinct follicle fates in mice, Biol Reprod
14;86(2):37, 2012.
27. Karl J, Capel B: Sertoli cells of the mouse testis originate from the
coelomic epithelium, Dev Biol 203(2):323–333, 1998.
28. Uhlenhaut NH, et al: Somatic sex reprogramming of adult ovaries to
testes by FOXL2 ablation, Cell 139(6):1130–1142, 2009.
29. Ellsworth BS, et al: The gonadotropin releasing hormone (GnRH)
receptor activating sequence (GRAS) is a composite regulatory ele-
ment that interacts with multiple classes of transcription factors
including Smads, AP-1 and a forkhead DNA binding protein, Mol Cell
Endocrinol 206(1-2):93–111, 2003.
30. Blount AL, et al: FoxL2 and Smad3 coordinately regulate follistatin
gene transcription, J Biol Chem 284(12):7631–7645, 2009.
31. Tran S, et al: SMADs and FOXL2 synergistically regulate murine
FSHbeta transcription via a conserved proximal promoter element,
Mol Endocrinol 25(7):1170–1183, 2011.
32. Kashimada K, et al: FOXL2 and BMP2 act cooperatively to regulate
follistatin gene expression during ovarian development, Endocrinology
152(1):272–280, 2011.
33. Shah SP, et al: Mutation of FOXL2 in granulosa-cell tumors of the
ovary, N Engl J Med 360(26):2719–2729, 2009.
34. White YA, et al: Oocyte formation by mitotically active germ
cells purified from ovaries of reproductive-age women, Nat Med
18(3):413–421, 2012.
35. McGee EA, Hsueh AJ: Initial and cyclic recruitment of ovarian fol-
licles, Endocr Rev 21(2):200–214, 2000.
36. Sullivan SD, Castrillon DH: Insights into primary ovarian insuffi-
ciency through genetically engineered mouse models, Semin Reprod
Med 29(4):283–298, 2011.
37. Young JM, McNeilly AS: Theca: the forgotten cell of the ovarian fol-
licle, Reproduction 140(4):489–504, 2011.
38. Wu X, et al: Interrelationship of growth differentiation factor 9 and
inhibin in early folliculogenesis and ovarian tumorigenesis in mice, Mol
Endocrinol 18(6):1509–1519, 2004.
39. Durlinger AL, Visser JA, Themmen AP: Regulation of ovarian func-
tion: the role of anti-Mullerian hormone, Reproduction 124(5):601–
609, 2002.
40. Anderson RA, Nelson SM, Wallace WH: Measuring anti-Mullerian
hormone for the assessment of ovarian reserve: when and for whom is
it indicated? Maturitas 71(1):28–33, 2012.
41. La Marca A, Volpe A: Anti-Mullerian hormone (AMH) in female
reproduction: is measurement of circulating AMH a useful tool? Clin
Endocrinol (Oxf) 64(6):603–610, 2006.
42. Matzuk MM, et al: Intercellular communication in the mammalian
ovary: oocytes carry the conversation, Science 296:2178–2180, 2002.
43. Boyer A, Goff AK, Boerboom D: WNT signaling in ovarian follicle
biology and tumorigenesis, Trends Endocrinol Metab 21(1):25–32,
2010.
44. Kumar TR, et al: Follicle stimulating hormone is required for ovar-
ian follicle maturation but not male fertility, Nat Genet 15:201–204,
1997.
45. Vale W, et al: The inhibin/activin family of hormones and growth fac-
tors, in peptide growth factors and their receptors II. In Sporn MB,
Roberts AB, editors: Berlin, 1990, Springer-Verlag, pp 211–248.
46. Zhu J, et al: Inhibin alpha-subunit N terminus interacts with
activin type IB receptor to disrupt activin signaling, J Biol Chem
287(11):8060–8070, 2012.
47. Lewis KA, et al: Betaglycan binds inhibin and can mediate functional
antagonism of activin signalling, Nature 404:411–414, 2000.
48. Knight PG, Glister C: TGF-beta superfamily members and ovarian
follicle development, Reproduction 132(2):191–206, 2006.
49. Matzuk MM, Kumar TR, Bradley A: Different phenotypes for
mice deficient in either activins or activin receptor type II, Nature
374:356–360, 1995.
50. Matzuk MM, et al: Functional analysis of activins in mammalian devel-
opment, Nature 374:354–356, 1995.
51. Matzuk MM, et al: Multiple defects and perinatally death in mice
deficient in follistatin, Nature 372:360–363, 1995.
52. Vassalli A, et al: Activin/inhibin βB subunit gene disruption leads to
defects in eyelid development and female reproduction, Genes Dev
8(4):414–427, 1994.
53. Pangas SA, et al: Intraovarian activins are required for female fertility,
Mol Endocrinol 21(10):2458–2471, 2007.
54. Nagashima T, et al: Connective tissue growth factor is required
for normal follicle development and ovulation, Mol Endocrinol
25(10):1740–1759, 2011.
55. Jorgez CJ, et al: Granulosa cell-specific inactivation of follistatin
causes female fertility defects, Mol Endocrinol 18(4):953–967, 2004.
56. Matzuk M, et al: α-Inhibin is a tumor-suppressor gene with gonadal
specificity in mice, Nature 360:313–319, 1992.
57. Myers M, et al: Loss of inhibin alpha uncouples oocyte-granulosa
cell dynamics and disrupts postnatal folliculogenesis, Dev Biol
334(2):458–467, 2009.
58. Coerver KA, et al: Activin signaling through activin receptor type II
causes the cachexia-like symptoms in inhibin-deficient mice, Mol
Endocrinol 10:534–543, 1996.

59. Li Q, et al: Redundant roles of SMAD2 and SMAD3 in ovarian granu-
losa cells in vivo, Mol Cell Biol 28(23):7001–7011, 2008.
60. Pangas SA, et al: Premature luteinization and cumulus cell defects in
ovarian-specific Smad4 knockout mice, Mol Endocrinol 20(6):1406–
1422, 2006.
61. Sugiura K, Su YQ, Eppig JJ: Does bone morphogenetic protein 6
(BMP6) affect female fertility in the mouse? Biol Reprod 83(6):997–
1004, 2010.
62. Yan C, et al: Synergistic roles of bone morphogenetic protein 15 and
growth differentiation factor 9 in ovarian function, Mol Endocrinol
15(6):854–866, 2001.
63. Middlebrook BS, et al: Smad1-Smad5 ovarian conditional knockout
mice develop a disease profile similar to the juvenile form of human
granulosa cell tumors, Endocrinology 150(12):5208–5217, 2009.
64. Conti M, et al: Novel signaling mechanisms in the ovary during oocyte
maturation and ovulation, Mol Cell Endocrinol 356(1-2):65–73, 2012.
65. Hsieh M, Zamah AM, Conti M: Epidermal growth factor-like growth
factors in the follicular fluid: role in oocyte development and matura-
tion, Semin Reprod Med 27(1):52–61, 2009.
66. Inoue A, et al: Contribution of the oocyte nucleus and cytoplasm to
the determination of meiotic and developmental competence in mice,
Hum Reprod 23(6):1377–1384, 2008.
67. Elvin JA, et al: Paracrine actions of growth differentiation factor-9 in
the mammalian ovary, Molecular Endocrinology 13:1035–1048, 1999.
68. Varani S, et al: Knockout of pentraxin 3, a downstream target of
growth differentiation factor-9, causes female subfertility, Molecular
Endocrinology 16:1154–1167, 2002.
69. Gui LM, Joyce IM: RNA interference evidence that growth differen-
tiation factor-9 mediates oocyte regulation of cumulus expansion in
mice, Biol Reprod 72(1):195–199, 2005.
70. Scaramuzzi RJ, et al: Regulation of folliculogenesis and the determina-
tion of ovulation rate in ruminants, Reprod Fertil Dev 23(3):444–467,
2011.
71. Pangas SA, Matzuk MM: The art and artifact of GDF9 activity: cumu-
lus expansion and the cumulus expansion-enabling factor, Biol Reprod
73(4):582–585, 2005.
72. Yoshino O, et al: 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 103(28):10678–10683, 2006.
73. Su YQ, et al: Synergistic roles of BMP15 and GDF9 in the devel-
opment and function of the oocyte-cumulus cell complex in mice:
genetic evidence for an oocyte-granulosa cell regulatory loop, Dev Biol
276(1):64–73, 2004.
74. Moore RK, Otsuka F, Shimasaki S: Molecular basis of bone morphoge-
netic protein-15 signaling in granulosa cells, J Biol Chem 278(1):304–
310, 2003.
75. Yi SE, et al: The type I BMP receptor BmprIB is essential for female
reproductive function, Proc Natl Acad Sci U S A 98(14):7994–7999,
2001.
76. Wu YT, et al: High bone morphogenetic protein-15 level in follicular
fluid is associated with high quality oocyte and subsequent embryonic
development, Hum Reprod 22(6):1526–1531, 2007.
77. McKenzie LJ, et al: Human cumulus granulosa cell gene expression: a
predictor of fertilization and embryo selection in women undergoing
IVF, Hum Reprod 19:2869–2874, 2004.
78. Cillo F, et al: Association between human oocyte developmental com-
petence and expression levels of some cumulus genes, Reproduction
134(5):645–650, 2007.
79. Assou S, et al: The human cumulus–oocyte complex gene-expression
profile, Hum Reprod 21(7):1705–1719, 2006.
80. Su YQ, et al: Synergistic roles of BMP15 and GDF9 in the devel-
opment and function of the oocyte-cumulus cell complex in mice:
genetic evidence for an oocyte-granulosa cell regulatory loop, Dev Biol
276(1):64–73, 2004.
81. White R, et al: The nuclear receptor co-repressor nrip1 (RIP140) is
essential for female fertility, Nat Med 6(12):1368–1374, 2000.
82. Burkart AD, et al: Repression of the inhibin alpha-subunit gene by the
transcription factor CCAAT/enhancer-binding protein-beta, Endocri-
nology 146(4):1909–1921, 2005.
83. Sterneck E, Tessarollo L, Johnson PF: An essential role for C/EBPβ in
female reproduction, Genes & Development 11:2153–2162, 1997.
84. Diaz FJ, Wigglesworth K, Eppig JJ: Oocytes determine cumulus cell
lineage in mouse ovarian follicles, J Cell Sci 120(Pt 8):1330–1340,
2007.
REFERENCES 140.e7
85. Polanco JC, Koopman P: Sry and the hesitant beginnings of male
development, Dev Biol 302(1):13–24, 2007.
86. DiNapoli L, Capel B: SRY and the standoff in sex determination, Mol
Endocrinol 22(1):1–9, 2008.
87. Sekido R, Lovell-Badge R: Sex determination and SRY: down to a wink
and a nudge? Trends Genet 25(1):19–29, 2009.
88. Kobayashi A, Behringer RR: Developmental genetics of the female
reproductive tract in mammals, Nat Rev Genet 4(12):969–980, 2003.
89. Masse J, et al: The developing female genital tract: from genetics to
epigenetics, Int J Dev Biol 53(2-3):411–424, 2009.
90. Orvis GD, Behringer RR: Cellular mechanisms of müllerian duct for-
mation in the mouse, Dev Biol 306(2):493–504, 2007.
91. Behringer RR, et al: Abnormal sexual development in transgenic
mice chronically expressing mullerian inhibiting substance, Nature
345(6271):167–170, 1990.
92. Behringer RR, Finegold MJ, Cate RL: müllerian-inhibiting substance
function during mammalian sexual development, Cell 79(3):415–425,
1994.
93. Josso N, et al: Anti-müllerian hormone: the Jost factor, Recent Prog
Horm Res 48:1–59, 1993.
94. di Clemente N, et al: Components of the anti-Mullerian hormone sig-
naling pathway in gonads, Mol Cell Endocrinol 211(1-2):9–14, 2003.
95. De Santa Barbara P, et al: Direct interaction of SRY-related protein
SOX9 and steroidogenic factor 1 regulates transcription of the human
anti-Mullerian hormone gene, Mol Cell Biol 18(11):6653–6665, 1998.
96. Nachtigal MW, et al: Wilms’ tumor 1 and Dax-1 modulate the orphan
nuclear receptor SF-1 in sex-specific gene expression, Cell 93(3):445–
454, 1998.
97. Orvis GD, et al: Functional redundancy of TGF-beta family type
I receptors and receptor-Smads in mediating anti-Mullerian hor-
mone-induced Mullerian duct regression in the mouse, Biol Reprod
78(6):994–1001, 2008.
98. Xavier F, Allard S: Anti-Mullerian hormone, beta-catenin and Mul-
lerian duct regression, Mol Cell Endocrinol 211(1-2):115–121, 2003.
99. Van der Ploeg LH, et al: A role for the melanocortin 4 receptor in sex-
ual function, Proc Natl Acad Sci U S A 99(17):11381–11386, 2002.
100. Vainio S, et al: Female development in mammals is regulated by Wnt-4
signalling, Nature 397(6718):405–409, 1999.
101. Stark K, et al: Epithelial transformation of metanephric mesenchyme
in the developing kidney regulated by Wnt-4, Nature 372(6507):679–
683, 1994.
102. Parr BA, McMahon AP: Sexually dimorphic development of the mam-
malian reproductive tract requires Wnt-7a, Nature 395(6703):707–
710, 1998.
103. Miller C, Sassoon DA: Wnt-7a maintains appropriate uterine pattern-
ing during the development of the mouse female reproductive tract,
Development 125(16):3201–3211, 1998.
104. Mericskay M, Kitajewski J, Sassoon D: Wnt5a is required for proper
epithelial-mesenchymal interactions in the uterus, Development
131(9):2061–2072, 2004.
105. Yamaguchi TP, et al: A Wnt5a pathway underlies outgrowth of mul-
tiple structures in the vertebrate embryo, Development 126(6):1211–
1223, 1999.
106. Wang H, Dey SK: Roadmap to embryo implantation: clues from
mouse models, Nat Rev Genet 7(3):185–199, 2006.
107. Paria BC, et al: Deciphering the cross-talk of implantation: advances
and challenges, Science 296(5576):2185–2188, 2002.
108. Varjosalo M, Taipale J: Hedgehog: functions and mechanisms, Genes
Dev 22(18):2454–2472, 2008.
109. Lee K, et al: Indian hedgehog is a major mediator of progesterone
signaling in the mouse uterus, Nat Genet 38(10):1204–1209, 2006.
110. Kurihara I, et al: COUP-TFII mediates progesterone regulation of
uterine implantation by controlling ER activity, PLoS Genet 3(6):e102,
2007.
111. Lee KY, et al: Bmp2 is critical for the murine uterine decidual
response, Mol Cell Biol 27(15):5468–5478, 2007.
112. Li Q, et al: Bone morphogenetic protein 2 functions via a conserved
signaling pathway involving Wnt4 to regulate uterine decidualization
in the mouse and the human, J Biol Chem 282(43):31725–31732,
2007.
113. Knofler M: Critical growth factors and signalling pathways controlling
human trophoblast invasion, Int J Dev Biol 54(2-3):269–280, 2010.
114. Lala PK, Hamilton GS: Growth factors, proteases and protease inhibi-
tors in the maternal-fetal dialogue, Placenta 17(8):545–555, 1996.
140.e8 REFERENCES
115. Cross JC, Anson-Cartwright L, Scott IC: Transcription factors under-
lying the development and endocrine functions of the placenta, Recent
Prog Horm Res 57:221–234, 2002.
116. Lala PK, Chakraborty C: Factors regulating trophoblast migration and
invasiveness: possible derangements contributing to pre-eclampsia and
fetal injury, Placenta 24(6):575–587, 2003.
117. Nadeem L, et al: Nodal signals through activin receptor-like kinase 7
to inhibit trophoblast migration and invasion: implication in the patho-
genesis of preeclampsia, Am J Pathol 178(3):1177–1189, 2011.
118. Carmeliet P, et al: Physiological consequences of loss of plasminogen
activator gene function in mice, Nature 368(6470):419–424, 1994.
119. Fitzgerald JS, et al: Trophoblast invasion: the role of intracellular cyto-
kine signalling via signal transducer and activator of transcription 3
(STAT3), Hum Reprod Update 14(4):335–344, 2008.
120. Tapia A, et al: Leukemia inhibitory factor promotes human first tri-
mester extravillous trophoblast adhesion to extracellular matrix and
secretion of tissue inhibitor of metalloproteinases-1 and -2, Hum
Reprod 23(8):1724–1732, 2008.
121. Munir S, et al: Nodal and ALK7 inhibit proliferation and induce apop-
tosis in human trophoblast cells, J Biol Chem 279(30):31277–31286,
2004.
122. Xu G, et al: Control of proliferation, migration, and invasiveness of
human extravillous trophoblast by decorin, a decidual product, Biol
Reprod 67(2):681–689, 2002.
123. Yang Q, et al: Smurf2 participates in human trophoblast cell inva-
sion by inhibiting TGF-beta type I receptor, J Histochem Cytochem
57(6):605–612, 2009.
124. Sjoblom C, Wikland M, Robertson SA: Granulocyte-macrophage
colony-stimulating factor promotes human blastocyst development
in vitro, Hum Reprod 14(12):3069–3076, 1999.
125. Gilchrist RB: Recent insights into oocyte-follicle cell interactions pro-
vide opportunities for the development of new approaches to in vitro
maturation, Reprod Fertil Dev 23(1):23–31, 2011.
126. Geisert R, et al: Interaction of the conceptus and endometrium to
establish pregnancy in mammals: role of interleukin 1beta, Cell Tissue
Res 349(3):825–838, 2012.
127. Ledee N, et al: New pre-conception immune biomarkers for clinical
practice: interleukin-18, interleukin-15 and TWEAK on the endome-
trial side, G-CSF on the follicular side, J Reprod Immunol 88(2):118–
123, 2011.
128. Brinsden PR, et al: Recombinant human leukemia inhibitory factor
does not improve implantation and pregnancy outcomes after assisted
reproductive techniques in women with recurrent unexplained
implantation failure, Fertil Steril 91(4 Suppl):1445–1447, 2009.
129. Angrist M, et al: Germline mutations in glial cell line-derived neuro-
trophic factor (GDNF) and RET in a Hirschsprung disease patient,
Nat Genet 14(3):341–344, 1996.