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Endometrial Development and Its Fine Structure

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Endometrial Gene Expression

Abstract

Reproduction is the biological process that produces new living individuals and essential for the continuity of species. In mammalian reproduction, the uterus plays a pivotal role as the organ that supports the development of offspring. The main subjects of this chapter are the development and structure of the uterus. To fully make sense of the overall structure of the uterus, the process through which urogenital systems arise must be understood. Thus, we start this chapter with embryology of the uterus. Furthermore, organ structure often dictates the function, and organ function dictates the structure. This bidirectional causality is particularly evident in the human uterus: The human uterus changes in morphology dramatically in response to endocrine cues. On the other hand, the anatomy of the uterus by design dictates its physiologic function. Thus, the aim of this chapter is to provide the foundation for the following chapters through the description of embryology, anatomy, and physiology of the uterus.

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References

  1. Kurita T. Developmental origin of vaginal epithelium. Differentiation. 2010;80(2–3):99–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Müller J. Bildungsgeschichte der Genitalien aus anatomischen Untersuchungen an Embryonen des Menschen und der Thiere; nebst einem Anhang über die chirurgische Behandlung der Hypospadia. Düsseldorf: Arnz; 1830.

    Book  Google Scholar 

  3. O’Rahilly R. The embryology and anatomy of the uterus. In: Wynn RM, editor. The uterus. International Academy of Pathology, Monograph. 14. Baltimore: The Williams & Wilkins Co.; 1973. p. 17–39.

    Google Scholar 

  4. Kobayashi A, Behringer RR. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet. 2003;4(12):969–80.

    Article  CAS  PubMed  Google Scholar 

  5. Robboy SJ, Kurita T, Baskin L, Cunha GR. New insights into human female reproductive tract development. Differentiation. 2017;97:9–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Grünwald P. The relation of the growing tip of the Müllerian duct to the Wolffian duct and its importance for the genesis of malformations. Anat Rec. 1941;81:1–19.

    Article  Google Scholar 

  7. Orvis GD, Behringer RR. Cellular mechanisms of Müllerian duct formation in the mouse. Dev Biol. 2007;306(2):493–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kurita T. Normal and abnormal epithelial differentiation in the female reproductive tract. Differentiation. 2011;82(3):117–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kurita T, Nakamura H. Embryology of the uterus. In: Aplin JD, Fazleabas AT, Glasser SR, Giudice LC, editors. Endometrium. 2nd ed. London, UK: Informa UK Ltd.; 2008. p. 1–18.

    Google Scholar 

  10. Koff AK. Development of the vagina in the human fetus. Contrib Embryol. 1933;24(140):59–91.

    CAS  PubMed  Google Scholar 

  11. Hashimoto R. Development of the human Müllerian duct in the sexually undifferentiated stage. Anat Rec A Discov Mol Cell Evol Biol. 2003;272(2):514–9.

    Article  PubMed  Google Scholar 

  12. Rey R, Josso N, Racine C. Sexual differentiation. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000.

    Google Scholar 

  13. Foster JW, Dominguez-Steglich MA, Guioli S, Kwok C, Weller PA, Stevanovic M, et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 1994;372(6506):525–30.

    Article  CAS  PubMed  Google Scholar 

  14. Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994;79(6):1111–20.

    Article  CAS  PubMed  Google Scholar 

  15. De Santa BP, Bonneaud N, Boizet B, Desclozeaux M, Moniot B, Sudbeck 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. 1998;18(11):6653–65.

    Article  Google Scholar 

  16. Nicol B, Yao HH. Building an ovary: insights into establishment of somatic cell lineages in the mouse. Sex Dev. 2014;8(5):243–51.

    Article  CAS  PubMed  Google Scholar 

  17. Pannetier M, Chassot AA, Chaboissier MC, Pailhoux E. Involvement of FOXL2 and RSPO1 in ovarian determination, development, and maintenance in mammals. Sex Dev. 2016;10(4):167–84.

    Article  CAS  PubMed  Google Scholar 

  18. Choussein S, Nasioudis D, Schizas D, Economopoulos KP. Mullerian dysgenesis: a critical review of the literature. Arch Gynecol Obstet. 2017;295(6):1369–81.

    Article  PubMed  Google Scholar 

  19. Patnaik SS, Brazile B, Dandolu V, Ryan PL, Liao J. Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome: a historical perspective. Gene. 2015;555(1):33–40.

    Article  CAS  PubMed  Google Scholar 

  20. Fontana L, Gentilin B, Fedele L, Gervasini C, Miozzo M. Genetics of Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Clin Genet. 2017;91(2):233–46.

    Article  CAS  PubMed  Google Scholar 

  21. Jacquinet A, Millar D, Lehman A. Etiologies of uterine malformations. Am J Med Genet A. 2016;170(8):2141–72.

    Article  PubMed  Google Scholar 

  22. The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, mullerian anomalies and intrauterine adhesions. Fertil Steril. 1988;49(6):944–55.

    Google Scholar 

  23. Mossman HW. Comparative anatomy. In: Wynn RM, editor. Biology of the uterus. New York: Plenum Press; 1977. p. 19–34.

    Chapter  Google Scholar 

  24. Maltais LJ, Blake JA, Eppig JT, Davisson MT. Rules and guidelines for mouse gene nomenclature: a condensed version. International Committee on Standardized Genetic Nomenclature for Mice. Genomics. 1997;45(2):471–6.

    Article  CAS  PubMed  Google Scholar 

  25. White JA, McAlpine PJ, Antonarakis S, Cann H, Eppig JT, Frazer K, et al. Guidelines for human gene nomenclature (1997). HUGO Nomenclature Committee. Genomics. 1997;45(2):468–71.

    Article  CAS  PubMed  Google Scholar 

  26. Huang CC, Orvis GD, Kwan KM, Behringer RR. Lhx1 is required in Mullerian duct epithelium for uterine development. Dev Biol. 2014;389(2):124–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kobayashi A, Kwan KM, Carroll TJ, McMahon AP, Mendelsohn CL, Behringer RR. Distinct and sequential tissue-specific activities of the LIM-class homeobox gene Lim1 for tubular morphogenesis during kidney development. Development. 2005;132(12):2809–23.

    Article  CAS  PubMed  Google Scholar 

  28. Kobayashi A, Shawlot W, Kania A, Behringer RR. Requirement of Lim1 for female reproductive tract development. Development. 2004;131(3):539–49.

    Article  CAS  PubMed  Google Scholar 

  29. Ledig S, Brucker S, Barresi G, Schomburg J, Rall K, Wieacker P. Frame shift mutation of LHX1 is associated with Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Hum Reprod. 2012;27(9):2872–5.

    Article  CAS  PubMed  Google Scholar 

  30. Davis RJ, Harding M, Moayedi Y, Mardon G. Mouse Dach1 and Dach2 are redundantly required for Mullerian duct development. Genesis. 2008;46(4):205–13.

    Article  CAS  PubMed  Google Scholar 

  31. Patel SR, Dressler GR. The genetics and epigenetics of kidney development. Semin Nephrol. 2013;33(4):314–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bouchard M, Souabni A, Mandler M, Neubuser A, Busslinger M. Nephric lineage specification by Pax2 and Pax8. Genes Dev. 2002;16(22):2958–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Torres M, Gomez-Pardo E, Dressler GR, Gruss P. Pax-2 controls multiple steps of urogenital development. Development. 1995;121(12):4057–65.

    CAS  PubMed  Google Scholar 

  34. Mansouri A, Chowdhury K, Gruss P. Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet. 1998;19(1):87–90.

    Article  CAS  PubMed  Google Scholar 

  35. Boualia SK, Gaitan Y, Tremblay M, Sharma R, Cardin J, Kania A, et al. A core transcriptional network composed of Pax2/8, Gata3 and Lim1 regulates key players of pro/mesonephros morphogenesis. Dev Biol. 2013;382(2):555–66.

    Article  CAS  PubMed  Google Scholar 

  36. Barua M, Stellacci E, Stella L, Weins A, Genovese G, Muto V, et al. Mutations in PAX2 associate with adult-onset FSGS. J Am Soc Nephrol. 2014;25(9):1942–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schimmenti LA. Renal coloboma syndrome. Eur J Hum Genet: EJHG. 2011;19(12):1207–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sanyanusin P, Schimmenti LA, McNoe LA, Ward TA, Pierpont ME, Sullivan MJ, et al. Mutation of the PAX2 gene in a family with optic nerve colobomas, renal anomalies and vesicoureteral reflux. Nat Genet. 1995;9(4):358–64.

    Article  CAS  PubMed  Google Scholar 

  39. Meeus L, Gilbert B, Rydlewski C, Parma J, Roussie AL, Abramowicz M, et al. Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. J Clin Endocrinol Metab. 2004;89(9):4285–91.

    Article  CAS  PubMed  Google Scholar 

  40. Madariaga L, Moriniere V, Jeanpierre C, Bouvier R, Loget P, Martinovic J, et al. Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes. Clin J Am Soc Nephrol. 2013;8(7):1179–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Miyamoto N, Yoshida M, Kuratani S, Matsuo I, Aizawa S. Defects of urogenital development in mice lacking Emx2. Development. 1997;124(9):1653–64.

    CAS  PubMed  Google Scholar 

  42. McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68(2):283–302.

    Article  CAS  PubMed  Google Scholar 

  43. Dollé P, Izpisua-Belmonte JC, Brown JM, Tickle C, Duboule D. HOX-4 genes and the morphogenesis of mammalian genitalia. Genes Dev. 1991;5(10):1767–75.

    Article  PubMed  Google Scholar 

  44. Ma L, Benson GV, Lim H, Dey SK, Maas RL. Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in Müllerian duct by the synthetic estrogen diethylstilbestrol (DES). Dev Biol. 1998;197(2):141–54.

    Article  CAS  PubMed  Google Scholar 

  45. Warot X, Fromental-Ramain C, Fraulob V, Chambon P, Dolle P. Gene dosage-dependent effects of the Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts. Development. 1997;124(23):4781–91.

    CAS  PubMed  Google Scholar 

  46. Raines AM, Adam M, Magella B, Meyer SE, Grimes HL, Dey SK, et al. Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts. Development. 2013;140(14):2942–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Benson GV, Lim H, Paria BC, Satokata I, Dey SK, Maas RL. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression. Development. 1996;122(9):2687–96.

    CAS  PubMed  Google Scholar 

  48. Gendron RL, Paradis H, Hsieh-Li HM, Lee DW, Potter SS, Markoff E. Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice. Biol Reprod. 1997;56(5):1097–105.

    Article  CAS  PubMed  Google Scholar 

  49. Branford WW, Benson GV, Ma L, Maas RL, Potter SS. Characterization of Hoxa-10/Hoxa-11 transheterozygotes reveals functional redundancy and regulatory interactions. Dev Biol. 2000;224(2):373–87.

    Article  CAS  PubMed  Google Scholar 

  50. Dolle P, Dierich A, LeMeur M, Schimmang T, Schuhbaur B, Chambon P, et al. Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs. Cell. 1993;75(3):431–41.

    Article  CAS  PubMed  Google Scholar 

  51. Roux M, Bouchard M, Kmita M. Multifaceted Hoxa13 function in urogenital development underlies the Hand-Foot-Genital Syndrome. Hum Mol Genet. 2019;28(10):1671–81.

    Article  PubMed  Google Scholar 

  52. Mortlock DP, Innis JW. Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet. 1997;15(2):179–80.

    Article  CAS  PubMed  Google Scholar 

  53. Innis JW. Hand-foot-genital syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, et al., editors. GeneReviews((R)). Seattle(WA): University of Washington, Seattle; 1993.

    Google Scholar 

  54. Goodman FR, Bacchelli C, Brady AF, Brueton LA, Fryns JP, Mortlock DP, et al. Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am J Hum Genet. 2000;67(1):197–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Debeer P, Bacchelli C, Scambler PJ, De Smet L, Fryns JP, Goodman FR. Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13. J Med Genet. 2002;39(11):852–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ekici AB, Strissel PL, Oppelt PG, Renner SP, Brucker S, Beckmann MW, et al. HOXA10 and HOXA13 sequence variations in human female genital malformations including congenital absence of the uterus and vagina. Gene. 2013;518(2):267–72.

    Article  CAS  PubMed  Google Scholar 

  57. Zhu Y, Cheng Z, Wang J, Liu B, Cheng L, Chen B, et al. A novel mutation of HOXA11 in a patient with septate uterus. Orphanet J Rare Dis. 2017;12(1):178.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Wilson JG, Warkany J. Malformations in the genito-urinary tract induced by maternal vitamin a deficiency in the rat. Am J Anat. 1948;83(3):357–407.

    Article  CAS  PubMed  Google Scholar 

  59. Mendelsohn C, Lohnes D, Decimo D, Lufkin T, LeMeur M, Chambon P, et al. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development. 1994;120(10):2749–71.

    CAS  PubMed  Google Scholar 

  60. Kastner P, Mark M, Ghyselinck N, Krezel W, Dupe V, Grondona JM, et al. Genetic evidence that the retinoid signal is transduced by heterodimeric RXR/RAR functional units during mouse development. Development. 1997;124(2):313–26.

    CAS  PubMed  Google Scholar 

  61. Marshall H, Morrison A, Studer M, Popperl H, Krumlauf R. Retinoids and Hox genes. FASEB J. 1996;10(9):969–78.

    Article  CAS  PubMed  Google Scholar 

  62. Langston AW, Gudas LJ. Retinoic acid and homeobox gene regulation. Curr Opin Genet Dev. 1994;4(4):550–5.

    Article  CAS  PubMed  Google Scholar 

  63. DiMartino JF, Selleri L, Traver D, Firpo MT, Rhee J, Warnke R, et al. The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. Blood. 2001;98(3):618–26.

    Article  CAS  PubMed  Google Scholar 

  64. Schnabel CA, Selleri L, Jacobs Y, Warnke R, Cleary ML. Expression of Pbx1b during mammalian organogenesis. Mech Dev. 2001;100(1):131–5.

    Article  CAS  PubMed  Google Scholar 

  65. Schnabel CA, Selleri L, Cleary ML. Pbx1 is essential for adrenal development and urogenital differentiation. Genesis. 2003;37(3):123–30.

    Article  CAS  PubMed  Google Scholar 

  66. Schnabel CA, Godin RE, Cleary ML. Pbx1 regulates nephrogenesis and ureteric branching in the developing kidney. Dev Biol. 2003;254(2):262–76.

    Article  CAS  PubMed  Google Scholar 

  67. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149(6):1192–205.

    Article  CAS  PubMed  Google Scholar 

  68. Wang J, Sinha T, Wynshaw-Boris A. Wnt signaling in mammalian development: lessons from mouse genetics. Cold Spring Harb Perspect Biol. 2012;4:a007963.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2016;36:1461.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling. Nature. 1999;397(6718):405–9.

    Article  CAS  PubMed  Google Scholar 

  71. Prunskaite-Hyyrylainen R, Skovorodkin I, Xu Q, Miinalainen I, Shan J, Vainio SJ. Wnt4 coordinates directional cell migration and extension of the Mullerian duct essential for ontogenesis of the female reproductive tract. Hum Mol Genet. 2016;25(6):1059–73.

    Article  PubMed  CAS  Google Scholar 

  72. Jeays-Ward K, Hoyle C, Brennan J, Dandonneau M, Alldus G, Capel B, et al. Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad. Development. 2003;130(16):3663–70.

    Article  CAS  PubMed  Google Scholar 

  73. Philibert P, Biason-Lauber A, Rouzier R, Pienkowski C, Paris F, Konrad D, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and mullerian duct abnormalities: a French collaborative study. J Clin Endocrinol Metab. 2008;93(3):895–900.

    Article  CAS  PubMed  Google Scholar 

  74. Philibert P, Biason-Lauber A, Gueorguieva I, Stuckens C, Pienkowski C, Lebon-Labich B, et al. Molecular analysis of WNT4 gene in four adolescent girls with mullerian duct abnormality and hyperandrogenism (atypical Mayer-Rokitansky-Kuster-Hauser syndrome). Fertil Steril. 2011;95(8):2683–6.

    Article  CAS  PubMed  Google Scholar 

  75. Green J, Nusse R, van Amerongen R. The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction. Cold Spring Harb Perspect Biol. 2014;6:a009175.

    Article  CAS  Google Scholar 

  76. Miller C, Pavlova A, Sassoon DA. Differential expression patterns of Wnt genes in the murine female reproductive tract during development and the estrous cycle. Mech Dev. 1998;76(1–2):91–9.

    Article  CAS  PubMed  Google Scholar 

  77. Mericskay M, Kitajewski J, Sassoon D. Wnt5a is required for proper epithelial-mesenchymal interactions in the uterus. Development. 2004;131(9):2061–72.

    Article  CAS  PubMed  Google Scholar 

  78. St-Jean G, Boyer A, Zamberlam G, Godin P, Paquet M, Boerboom D. Targeted ablation of Wnt4 and Wnt5a in Mullerian duct mesenchyme impedes endometrial gland development and causes partial Mullerian agenesis. Biol Reprod. 2019;100(1):49–60.

    Article  PubMed  Google Scholar 

  79. Person AD, Beiraghi S, Sieben CM, Hermanson S, Neumann AN, Robu ME, et al. WNT5A mutations in patients with autosomal dominant Robinow syndrome. Dev Dyn. 2010;239(1):327–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Takasato M, Little MH. The origin of the mammalian kidney: implications for recreating the kidney in vitro. Development. 2015;142(11):1937–47.

    Article  CAS  PubMed  Google Scholar 

  81. Dressler GR. Advances in early kidney specification, development and patterning. Development. 2009;136(23):3863–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Carroll TJ, Park JS, Hayashi S, Majumdar A, McMahon AP. Wnt9b plays a central role in the regulation of mesenchymal to transitions underlying organogenesis of the mammalian urogenital. Dev Cell. 2005;9(2):283–92.

    Article  CAS  PubMed  Google Scholar 

  83. Waschk DE, Tewes AC, Romer T, Hucke J, Kapczuk K, Schippert C, et al. Mutations in WNT9B are associated with Mayer-Rokitansky-Kuster-Hauser syndrome. Clin Genet. 2016;89(5):590–6.

    Article  CAS  PubMed  Google Scholar 

  84. Lokmane L, Heliot C, Garcia-Villalba P, Fabre M, Cereghini S. vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis. Development. 2010;137(2):347–57.

    Article  CAS  PubMed  Google Scholar 

  85. Coffinier C, Barra J, Babinet C, Yaniv M. Expression of the vHNF1/HNF1beta homeoprotein gene during mouse organogenesis. Mech Dev. 1999;89(1–2):211–3.

    Article  CAS  PubMed  Google Scholar 

  86. Schimke RN, King CR. Hereditary urogenital adysplasia. Clin Genet. 1980;18(6):417–20.

    Article  CAS  PubMed  Google Scholar 

  87. Verhave JC, Bech AP, Wetzels JF, Nijenhuis T. Hepatocyte nuclear factor 1beta-associated kidney disease: more than renal cysts and diabetes. J Am Soc Nephrol. 2016;27(2):345–53.

    Article  CAS  PubMed  Google Scholar 

  88. Lindner TH, Njolstad PR, Horikawa Y, Bostad L, Bell GI, Sovik O. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum Mol Genet. 1999;8(11):2001–8.

    Article  CAS  PubMed  Google Scholar 

  89. Iwasaki N, Okabe I, Momoi MY, Ohashi H, Ogata M, Iwamoto Y. Splice site mutation in the hepatocyte nuclear factor-1 beta gene, IVS2nt + 1G > A, associated with maturity-onset diabetes of the young, renal dysplasia and bicornuate uterus. Diabetologia. 2001;44(3):387–8.

    Article  CAS  PubMed  Google Scholar 

  90. Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140(7):510–7.

    Article  CAS  PubMed  Google Scholar 

  91. Grote D, Boualia SK, Souabni A, Merkel C, Chi X, Costantini F, et al. Gata3 acts downstream of beta-catenin signaling to prevent ectopic metanephric kidney induction. PLoS Genet. 2008;4(12):e1000316.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Belge H, Dahan K, Cambier JF, Benoit V, Morelle J, Bloch J, et al. Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome. Nephrol Dial Transplant. 2017;32(5):830–7.

    CAS  PubMed  Google Scholar 

  93. Hernandez AM, Villamar M, Rosello L, Moreno-Pelayo MA, Moreno F, Del Castillo I. Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations. Am J Med Genet A. 2007;143A(7):757–62.

    Article  CAS  PubMed  Google Scholar 

  94. Iizuka-Kogo A, Ishidao T, Akiyama T, Senda T. Abnormal development of urogenital organs in Dlgh1-deficient mice. Development. 2007;134(9):1799–807.

    Article  CAS  PubMed  Google Scholar 

  95. Jamin SP, Arango NA, Mishina Y, Hanks MC, Behringer RR. Requirement of Bmpr1a for Müllerian duct regression during male sexual development. Nat Genet. 2002;32(3):408–10.

    Article  CAS  PubMed  Google Scholar 

  96. Orvis GD, Jamin SP, Kwan KM, Mishina Y, Kaartinen VM, Huang S, et al. Functional redundancy of tgf-Beta family type I receptors and receptor-smads in mediating anti-mullerian hormone-induced mullerian duct regression in the mouse. Biol Reprod. 2008;78(6):994–1001.

    Article  CAS  PubMed  Google Scholar 

  97. Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Moustakas A, Heldin CH. The regulation of TGF beta signal transduction. Development. 2009;136(22):3699–714.

    Article  CAS  PubMed  Google Scholar 

  99. Kobayashi A, Stewart CA, Wang Y, Fujioka K, Thomas NC, Jamin SP, et al. beta-Catenin is essential for Mullerian duct regression during male sexual differentiation. Development. 2011;138(10):1967–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Parr BA, McMahon AP. Sexually dimorphic development of the mammalian reproductive tract requires Wnt-7a. Nature. 1998;395(6703):707–10.

    Article  CAS  PubMed  Google Scholar 

  101. Deutscher E, Hung-Chang YH. Essential roles of mesenchyme-derived beta-catenin in mouse Müllerian duct morphogenesis. Dev Biol. 2007;307(2):227–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tanwar PS, Zhang L, Tanaka Y, Taketo MM, Donahoe PK, Teixeira JM. Focal Mullerian duct retention in male mice with constitutively activated beta-catenin expression in the Mullerian duct mesenchyme. Proc Natl Acad Sci U S A. 2010;107(37):16142–7.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Park JH, Tanaka Y, Arango NA, Zhang L, Benedict LA, Roh MI, et al. Induction of WNT inhibitory factor 1 expression by Mullerian inhibiting substance/anti-Mullerian hormone in the Mullerian duct mesenchyme is linked to Mullerian duct regression. Dev Biol. 2014;386(1):227–36.

    Article  CAS  PubMed  Google Scholar 

  104. Mullen RD, Wang Y, Liu B, Moore EL, Behringer RR. Osterix functions downstream of anti-Mullerian hormone signaling to regulate Mullerian duct regression. Proc Natl Acad Sci U S A. 2018;115(33):8382–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Josso N, Belville C, di Clemente N, Picard JY. AMH and AMH receptor defects in persistent Mullerian duct syndrome. Hum Reprod Update. 2005;11(4):351–6.

    Article  CAS  PubMed  Google Scholar 

  106. Knebelmann B, Boussin L, Guerrier D, Legeai L, Kahn A, Josso N, et al. Anti-Mullerian hormone Bruxelles: a nonsense mutation associated with the persistent Mullerian duct syndrome. Proc Natl Acad Sci U S A. 1991;88(9):3767–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Imbeaud S, Faure E, Lamarre I, Mattei MG, di Clemente N, Tizard R, et al. Insensitivity to anti-mullerian hormone due to a mutation in the human anti-mullerian hormone receptor. Nat Genet. 1995;11(4):382–8.

    Article  CAS  PubMed  Google Scholar 

  108. Laronda MM, Unno K, Ishi K, Serna VA, Butler LM, Mills AA, et al. Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Mullerian duct epithelium. Dev Biol. 2013;381(1):5–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kurita T, Mills AA, Cunha GR. Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis. Development. 2004;131(7):1639–49.

    Article  CAS  PubMed  Google Scholar 

  110. Kurita T, Cunha GR, Robboy SJ, Mills AA, Medina RT. Differential expression of p63 isoforms in female reproductive organs. Mech Dev. 2005;122(9):1043–55.

    Article  CAS  PubMed  Google Scholar 

  111. Cunha GR, Kurita T, Cao M, Shen J, Robboy S, Baskin L. Molecular mechanisms of development of the human fetal female reproductive tract. Differentiation. 2017;97:54–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Valdés-Dapena MA. The development of the uterus in late fetal life, infancy, and childhood. In: Norris HJ, Hertig AT, Abell MR, editors. The uterus. Baltimore: The Williams & Wilkins Company; 1973.

    Google Scholar 

  113. Haber HP, Mayer EI. Ultrasound evaluation of uterine and ovarian size from birth to puberty. Pediatr Radiol. 1994;24(1):11–3.

    Article  CAS  PubMed  Google Scholar 

  114. Salardi S, Orsini LF, Cacciari E, Bovicelli L, Tassoni P, Reggiani A. Pelvic ultrasonography in premenarcheal girls: relation to puberty and sex hormone concentrations. Arch Dis Child. 1985;60(2):120–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hagen CP, Mouritsen A, Mieritz MG, Tinggaard J, Wohlfahrt-Veje C, Fallentin E, et al. Uterine volume and endometrial thickness in healthy girls evaluated by ultrasound (3-dimensional) and magnetic resonance imaging. Fertil Steril. 2015;104(2):452–9.e2.

    Article  PubMed  Google Scholar 

  116. Holm K, Laursen EM, Brocks V, Muller J. Pubertal maturation of the internal genitalia: an ultrasound evaluation of 166 healthy girls. Ultrasound Obstet Gynecol. 1995;6(3):175–81.

    Article  CAS  PubMed  Google Scholar 

  117. Ivarsson SA, Nilsson KO, Persson PH. Ultrasonography of the pelvic organs in prepubertal and postpubertal girls. Arch Dis Child. 1983;58(5):352–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Maybin JA, Critchley HO. Menstrual physiology: implications for endometrial pathology and beyond. Hum Reprod Update. 2015;21(6):748–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–3.

    Article  CAS  PubMed  Google Scholar 

  120. Duggan MA, Brashert P, Ostor A, Scurry J, Billson V, Kneafsey P, et al. The accuracy and interobserver reproducibility of endometrial dating. Pathology. 2001;33(3):292–7.

    Article  CAS  PubMed  Google Scholar 

  121. Li TC, Dockery P, Rogers AW, Cooke ID. How precise is histologic dating of endometrium using the standard dating criteria? Fertil Steril. 1989;51(5):759–63.

    Article  CAS  PubMed  Google Scholar 

  122. Brosens JJ, Gellersen B. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35(6):851–905.

    Article  PubMed  CAS  Google Scholar 

  123. Rock J, Bartlett MK. Biopsy studies of human endometrium: criteria of dating and information about amenorrhea, menorrhagia and time of ovulation. J Am Med Assoc. 1937;108(24):2022–8.

    Article  CAS  PubMed  Google Scholar 

  124. Maslar IA, Riddick DH. Prolactin production by human endometrium during the normal menstrual cycle. Am J Obstet Gynecol. 1979;135(6):751–4.

    Article  CAS  PubMed  Google Scholar 

  125. Rutanen EM, Koistinen R, Sjoberg J, Julkunen M, Wahlstrom T, Bohn H, et al. Synthesis of placental protein 12 by human endometrium. Endocrinology. 1986;118(3):1067–71.

    Article  CAS  PubMed  Google Scholar 

  126. van der Horst CJ. The placentation of elephantulus. Transactions of the Royal Society of South Africa. 1949;32(5):435–629.

    Article  Google Scholar 

  127. Carter AM. Classics revisited: C. J. van der Horst on pregnancy and menstruation in elephant shrews. Placenta. 2018;67:24–30.

    Article  CAS  PubMed  Google Scholar 

  128. Bellofiore N, Ellery SJ, Mamrot J, Walker DW, Temple-Smith P, Dickinson H. First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus). Am J Obstet Gynecol. 2017;216(1):40 e1–e11.

    Article  Google Scholar 

  129. Rasweiler JJ, Badwaik NK. 5 - Anatomy and physiology of the female reproductive tract. In: Crichton EG, Krutzsch PH, editors. Reproductive biology of bats. London: Academic Press; 2000. p. 157–219.

    Chapter  Google Scholar 

  130. Sato T, Fukazawa Y, Kojima H, Enari M, Iguchi T, Ohta Y. Apoptotic cell death during the estrous cycle in the rat uterus and vagina. Anat Rec. 1997;248(1):76–83.

    Article  CAS  PubMed  Google Scholar 

  131. Kurita T, Wang YZ, Donjacour AA, Zhao C, Lydon JP, O’Malley BW, et al. Paracrine regulation of apoptosis by steroid hormones in the male and female reproductive system. Cell Death Differ. 2001;8(2):192–200.

    Article  CAS  PubMed  Google Scholar 

  132. Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol. 2013;14(6):329–40.

    Article  CAS  PubMed  Google Scholar 

  133. Rezza A, Sennett R, Rendl M. Adult stem cell niches: cellular and molecular components. Curr Top Dev Biol. 2014;107:333–72.

    Article  CAS  PubMed  Google Scholar 

  134. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.

    Article  CAS  PubMed  Google Scholar 

  135. Shay JW. Telomeres and aging. Curr Opin Cell Biol. 2018;52:1–7.

    Article  CAS  PubMed  Google Scholar 

  136. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43(2 Pt 1):405–13.

    Article  CAS  PubMed  Google Scholar 

  137. Olovnikov AM. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol. 1973;41(1):181–90.

    Article  CAS  PubMed  Google Scholar 

  138. Gire V, Dulic V. Senescence from G2 arrest, revisited. Cell cycle (Georgetown, Tex.). 2015;14(3):297–304.

    Article  CAS  Google Scholar 

  139. Jabbour HN, Kelly RW, Fraser HM, Critchley HO. Endocrine regulation of menstruation. Endocr Rev. 2006;27(1):17–46.

    Article  CAS  PubMed  Google Scholar 

  140. Padykula HA. Regeneration in the primate uterus: the role of stem cells. Ann N Y Acad Sci. 1991;622:47–56.

    Article  CAS  PubMed  Google Scholar 

  141. Tempest N, Maclean A, Hapangama DK. Endometrial stem cell markers: current concepts and unresolved questions. Int J Mol Sci. 2018;19(10):3240.

    Article  PubMed Central  CAS  Google Scholar 

  142. Gargett CE, Chan RW, Schwab KE. Endometrial stem cells. Curr Opin Obstet Gynecol. 2007;19(4):377–83.

    Article  PubMed  Google Scholar 

  143. Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, et al. Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium. Cell Rep. 2018;24(7):1777–89.

    Article  CAS  PubMed  Google Scholar 

  144. Valentijn AJ, Saretzki G, Tempest N, Critchley HO, Hapangama DK. Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis. Hum Reprod. 2015;30(12):2816–28.

    CAS  PubMed  Google Scholar 

  145. Tanaka M, Kyo S, Takakura M, Kanaya T, Sagawa T, Yamashita K, et al. Expression of telomerase activity in human endometrium is localized to epithelial glandular cells and regulated in a menstrual phase-dependent manner correlated with cell proliferation. Am J Pathol. 1998;153(6):1985–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Yokoyama Y, Takahashi Y, Shinohara A, Lian Z, Xiaoyun W, Niwa K, et al. Telomerase activity is found in the epithelial cells but not in the stromal cells in human endometrial cell culture. Mol Hum Reprod. 1998;4(10):985–9.

    Article  CAS  PubMed  Google Scholar 

  147. Vue Z, Gonzalez G, Stewart CA, Mehra S, Behringer RR. Volumetric imaging of the developing prepubertal mouse uterine epithelium using light sheet microscopy. Mol Reprod Dev. 2018;85(5):397–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gray CA, Bartol FF, Tarleton BJ, Wiley AA, Johnson GA, Bazer FW, et al. Developmental biology of uterine glands. Biol Reprod. 2001;65(5):1311–23.

    Article  CAS  PubMed  Google Scholar 

  149. Yuan J, Deng W, Cha J, Sun X, Borg JP, Dey SK. Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. Nat Commun. 2018;9(1):603.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Tanaka M, Kyo S, Kanaya T, Yatabe N, Nakamura M, Maida Y, et al. Evidence of the monoclonal composition of human endometrial epithelial glands and mosaic pattern of clonal distribution in luminal epithelium. Am J Pathol. 2003;163(1):295–301.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Bhatt H, Brunet LJ, Stewart CL. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation. Proc Natl Acad Sci U S A. 1991;88(24):11408–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–9.

    Article  CAS  PubMed  Google Scholar 

  153. Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology. 2000;141(12):4365–72.

    Article  CAS  PubMed  Google Scholar 

  154. Kobayashi R, Terakawa J, Kato Y, Azimi S, Inoue N, Ohmori Y, et al. The contribution of leukemia inhibitory factor (LIF) for embryo implantation differs among strains of mice. Immunobiology. 2014;219(7):512–21.

    Article  CAS  PubMed  Google Scholar 

  155. Jeong JW, Lee HS, Franco HL, Broaddus RR, Taketo MM, Tsai SY, et al. beta-catenin mediates glandular formation and dysregulation of beta-catenin induces hyperplasia formation in the murine uterus. Oncogene. 2009;28(1):31–40.

    Article  CAS  PubMed  Google Scholar 

  156. Franco HL, Dai D, Lee KY, Rubel CA, Roop D, Boerboom D, 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. 2011;25(4):1176–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Miller C, Sassoon DA. Wnt-7a maintains appropriate uterine patterning during the development of the mouse female reproductive tract. Development. 1998;125(16):3201–11.

    CAS  PubMed  Google Scholar 

  158. Dunlap KA, Filant J, Hayashi K, Rucker EB, 3rd, Song G, Deng JM, et al. Postnatal deletion of Wnt7a inhibits uterine gland morphogenesis and compromises adult fertility in mice. Biol Reprod. 2011;85(2):386–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Goad J, Ko YA, Kumar M, Syed SM, Tanwar PS. Differential Wnt signaling activity limits epithelial gland development to the anti-mesometrial side of the mouse uterus. Dev Biol. 2017;423(2):138–51.

    Article  CAS  PubMed  Google Scholar 

  160. Shelton DN, Fornalik H, Neff T, Park SY, Bender D, DeGeest K, et al. The role of LEF1 in endometrial gland formation and carcinogenesis. PLoS One. 2012;7(7):e40312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Terakawa J, Serna VA, Taketo MM, Daikoku T, Suarez A, Kurita T. Ovarian-insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities. Proc Natl Acad Sci U S A. 2019;116(10):4528–37.

    Article  CAS  Google Scholar 

  162. Oh SJ, Shin JH, Kim TH, Lee HS, Yoo JY, Ahn JY, et al. beta-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition. J Pathol. 2013;231(2):210–22.

    Article  CAS  PubMed  Google Scholar 

  163. Farah O, Biechele S, Rossant J, Dufort D. Porcupine-dependent Wnt signaling controls stromal proliferation and endometrial gland maintenance through the action of distinct WNTs. Dev Biol. 2017;422(1):58–69.

    Article  CAS  PubMed  Google Scholar 

  164. Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, et al. LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and Wnt/PCP signalling. EMBO Rep. 2011;12(10):1055–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sone M, Oyama K, Mohri Y, Hayashi R, Clevers H, Nishimori K. LGR4 expressed in uterine epithelium is necessary for uterine gland development and contributes to decidualization in mice. FASEB J. 2013;27(12):4917–28.

    Article  CAS  PubMed  Google Scholar 

  166. Hirate Y, Suzuki H, Kawasumi M, Takase HM, Igarashi H, Naquet P, et al. Mouse Sox17 haploinsufficiency leads to female subfertility due to impaired implantation. Sci Rep. 2016;6:24171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Guimaraes-Young A, Neff T, Dupuy AJ, Goodheart MJ. Conditional deletion of Sox17 reveals complex effects on uterine adenogenesis and function. Dev Biol. 2016;414(2):219–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Kurita T, Cooke PS, Cunha GR. Epithelial-stromal tissue interaction in paramesonephric (Mullerian) epithelial differentiation. Dev Biol. 2001;240(1):194–211.

    Article  CAS  PubMed  Google Scholar 

  169. Kurita T, Lee KJ, Cooke PS, Taylor JA, Lubahn DB, Cunha GR. Paracrine regulation of epithelial progesterone receptor by estradiol in the mouse female reproductive tract. Biol Reprod. 2000;62(4):821–30.

    Article  CAS  PubMed  Google Scholar 

  170. Engert S, Burtscher I, Liao WP, Dulev S, Schotta G, Lickert H. Wnt/beta-catenin signalling regulates Sox17 expression and is essential for organizer and endoderm formation in the mouse. Development. 2013;140(15):3128–38.

    Article  CAS  PubMed  Google Scholar 

  171. Sinner D, Rankin S, Lee M, Zorn AM. Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development. 2004;131(13):3069–80.

    Article  CAS  PubMed  Google Scholar 

  172. Robledo RF, Rajan L, Li X, Lufkin T. The Dlx5 and Dlx6 homeobox genes are essential for craniofacial, axial, and appendicular skeletal development. Genes Dev. 2002;16(9):1089–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Bellessort B, Le Cardinal M, Bachelot A, Narboux-Neme N, Garagnani P, Pirazzini C, et al. Dlx5 and Dlx6 control uterine adenogenesis during post-natal maturation: possible consequences for endometriosis. Hum Mol Genet. 2016;25(1):97–108.

    Article  CAS  PubMed  Google Scholar 

  174. Rakowiecki S, Epstein DJ. Divergent roles for Wnt/beta-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation. Development. 2013;140(8):1730–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Cancer Genome Atlas Research N, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67–73.

    Article  CAS  Google Scholar 

  176. Chang HJ, Shin HS, Kim TH, Yoo JY, Teasley HE, Zhao JJ, et al. Pik3ca is required for mouse uterine gland development and pregnancy. PLoS One. 2018;13(1):e0191433.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Fehon RG, McClatchey AI, Bretscher A. Organizing the cell cortex: the role of ERM proteins. Nat Rev. 2010;11(4):276–87.

    Article  CAS  Google Scholar 

  178. McClatchey AI, Giovannini M. Membrane organization and tumorigenesis--the NF2 tumor suppressor, Merlin. Genes Develop. 2005;19(19):2265–77.

    Article  CAS  PubMed  Google Scholar 

  179. Lopez EW, Vue Z, Broaddus RR, Behringer RR, Gladden AB. The ERM family member Merlin is required for endometrial gland morphogenesis. Dev Biol. 2018;442(2):301–14.

    Article  CAS  PubMed  Google Scholar 

  180. Cooke PS, Spencer TE, Bartol FF, Hayashi K. Uterine glands: development, function and experimental model systems. Mol Hum Reprod. 2013;19(9):547–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Hou X, Tan Y, Li M, Dey SK, Das SK. Canonical Wnt signaling is critical to estrogen-mediated uterine growth. Mol Endocrinol. 2004;18(12):3035–49.

    Article  CAS  PubMed  Google Scholar 

  182. Hayashi K, Erikson DW, Tilford SA, Bany BM, Maclean JA 2nd, Rucker EB 3rd, et al. Wnt genes in the mouse uterus: potential regulation of implantation. Biol Reprod. 2009;80(5):989–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Cooke PS, Buchanan DL, Young P, Setiawan T, Brody J, Korach KS, et al. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci U S A. 1997;94(12):6535–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Kurita T, Young P, Brody JR, Lydon JP, O’Malley BW, Cunha GR. Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis. Endocrinology. 1998;139(11):4708–13.

    Article  CAS  PubMed  Google Scholar 

  185. Kurita T, Lee KJ, Cooke PS, Lydon JP, Cunha GR. Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus. Biol Reprod. 2000;62(4):831–8.

    Article  CAS  PubMed  Google Scholar 

  186. Buchanan DL, Setiawan T, Lubahn DB, Taylor JA, Kurita T, Cunha GR, et al. Tissue compartment-specific estrogen receptor-alpha participation in the mouse uterine epithelial secretory response. Endocrinology. 1999;140(1):484–91.

    Article  CAS  PubMed  Google Scholar 

  187. Winuthayanon W, Hewitt SC, Orvis GD, Behringer RR, Korach KS. Uterine epithelial estrogen receptor alpha is dispensable for proliferation but essential for complete biological and biochemical responses. Proc Natl Acad Sci U S A. 2010;107(45):19272–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Mehta FF, Son J, Hewitt SC, Jang E, Lydon JP, Korach KS, et al. Distinct functions and regulation of epithelial progesterone receptor in the mouse cervix, vagina, and uterus. Oncotarget. 2016;7(14):17455–67.

    Google Scholar 

  189. Kaufman RH, Adam E, Binder GL, Gerthoffer E. Upper genital tract changes and pregnancy outcome in offspring exposed in utero to diethylstilbestrol. Am J Obstet Gynecol. 1980;137(3):299–308.

    Article  CAS  PubMed  Google Scholar 

  190. Kaufman RH, Binder GL, Gray PM Jr, Adam E. Upper genital tract changes associated with exposure in utero to diethylstilbestrol. Am J Obstet Gynecol. 1977;128(1):51–9.

    Article  CAS  PubMed  Google Scholar 

  191. Dodds EC, Golberg L, Lawson W, Robinson R. synthetic oestrogenic compounds related to stilbene and diphenylethane. Part I Proceedings of the Royal Society of London Series B, Biological Sciences. 1939;127(847):140–67.

    Article  Google Scholar 

  192. Dodds EC, Goldberg L, Lawson W, Robinson R. OEstrogenic activity of certain synthetic compounds. Nature. 1938;141(3562):247–8.

    Article  CAS  Google Scholar 

  193. Berger MJ, Goldstein DP. Impaired reproductive performance in DES-exposed women. Obstet Gynecol. 1980;55(1):25–7.

    CAS  PubMed  Google Scholar 

  194. Fernandez H, Garbin O, Castaigne V, Gervaise A, Levaillant JM. Surgical approach to and reproductive outcome after surgical correction of a T-shaped uterus. Hum Reprod (Oxford, England). 2011;26(7):1730–4.

    Article  Google Scholar 

  195. Dieckmann WJ, Davis ME, Rynkiewicz LM, Pottinger RE. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol. 1953;66(5):1062–81.

    Article  CAS  PubMed  Google Scholar 

  196. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284(15):878–81.

    Article  CAS  PubMed  Google Scholar 

  197. Greenwald P, Barlow JJ, Nasca PC, Burnett WS. Vaginal cancer after maternal treatment with synthetic estrogens. N Engl J Med. 1971;285(7):390–2.

    Article  CAS  PubMed  Google Scholar 

  198. Giusti RM, Iwamoto K, Hatch EE. Diethylstilbestrol revisited: a review of the long-term health effects. Ann Intern Med. 1995;122(10):778–88.

    Article  CAS  PubMed  Google Scholar 

  199. Robboy SJ, Szyfelbein WM, Goellner JR, Kaufman RH, Taft PD, Richard RM, et al. Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project. Am J Obstet Gynecol. 1981;140(5):579–86.

    Article  CAS  PubMed  Google Scholar 

  200. Robboy SJ, Young RH, Welch WR, Truslow GY, Prat J, Herbst AL, et al. Atypical vaginal adenosis and cervical ectropion. Association with clear cell adenocarcinoma in diethylstilbestrol-exposed offspring. Cancer. 1984;54(5):869–75.

    Article  CAS  PubMed  Google Scholar 

  201. Laronda MM, Unno K, Butler LM, Kurita T. The development of cervical and vaginal adenosis as a result of diethylstilbestrol exposure in utero. Differentiation. 2012;84(3):252–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Terakawa J, Rocchi A, Serna VA, Bottinger EP, Graff JM, Kurita T. FGFR2IIIb-MAPK activity is required for epithelial cell fate decision in the lower Mullerian duct. Mol Endocrinol. 2016;30(7):783–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Kurita T, Cunha GR. Roles of p63 in differentiation of Mullerian duct epithelial cells. Ann N Y Acad Sci. 2001;948:9–12.

    Article  CAS  PubMed  Google Scholar 

  204. Miller C, Degenhardt K, Sassoon DA. Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis. Nat Genet. 1998;20(3):228–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Couse JF, Dixon D, Yates M, Moore AB, Ma L, Maas R, et al. Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract. Dev Biol. 2001;238(2):224–38.

    Article  CAS  PubMed  Google Scholar 

  206. Kurita T, Medina R, Schabel AB, Young P, Gama P, Parekh TV, et al. The activation function-1 domain of estrogen receptor alpha in uterine stromal cells is required for mouse but not human uterine epithelial response to estrogen. Differentiation. 2005;73(6):313–22.

    Article  CAS  PubMed  Google Scholar 

  207. Liu S, Gao X, Qin Y, Liu W, Huang T, Ma J, et al. Nonsense mutation of EMX2 is potential causative for uterus didelphysis: first molecular explanation for isolated incomplete mullerian fusion. Fertil Steril. 2015;103(3):769–74.e2.

    Article  CAS  PubMed  Google Scholar 

  208. Slavotinek A, Risolino M, Losa M, Cho MT, Monaghan KG, Schneidman-Duhovny D, et al. De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects. Hum Mol Genet. 2017;26(24):4849–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman. N Engl J Med. 2004;351(8):792–8.

    Article  CAS  PubMed  Google Scholar 

  210. Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle EJ. WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report. Hum Reprod. 2007;22(1):224–9.

    Article  CAS  PubMed  Google Scholar 

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The authors acknowledge Ms. Vanida Ann Serna for editing this book chapter.

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Kurita, T., Terakawa, J. (2020). Endometrial Development and Its Fine Structure. In: Kwak-Kim, J. (eds) Endometrial Gene Expression. Springer, Cham. https://doi.org/10.1007/978-3-030-28584-5_1

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