1. Chapter 38 Embryo Implantation
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

2. FIGURE 38.1 Increased endometrial vascular permeability upon attachment and implantation in the mouse. This figure is reproduced in color in the color plate section. (A) Transverse section of uterus on day 5 (D5) early morning (00:30) of pregnancy showing implantation at the antimesometrial pole within a crypt (arrowhead). This section also shows weak alkaline phosphatase activity in the uterine stroma (black, arrow). Note the edema in the outer areas of the mucosa, contrasting with the closely packed cells around the uterine lumen (presumptive primary decidual zone). Le, luminal epithelium; ge, glandular epithelium; s, stroma; myo, myometrium; M, mesometrial pole; AM, antimesometrial pole. (Source: Reprinted with permission from Ref. 2.) (B) Increased vascular permeability at the sites of blastocyst attachment with the uterine luminal epithelium was detected after an intravenous injection of a blue dye (Chicago Blue B6) solution in mice at midnight of day 4 (D4) and day 8 (D8) of pregnancy. On day 4, distinct blue bands (dark bands in this picture) indicate that the attachment process has been initiated.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

3. FIGURE 38.2 A scheme depicting modulation of the window of receptivity in the P4-primed uterus in response to changing estrogen levels in the mouse. This scheme shows that estrogen at a low threshold level extends the window of uterine receptivity for implantation, but higher levels rapidly close this window, transforming the uterus into a refractory state. Source: Reprinted with permission from Ref. 5.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

4. FIGURE 38.3 Strategies for embryonic diapause for marsupials and carnivores. In the marsupial model, which exhibits both obligate and facultative delay, suckling stimulus and increased melatonin secretion associated with nocturnal periods in excess of the summer solstice upregulate prolactin, which then inhibits luteal activation, thereby initiating and maintaining diapause. In the carnivore model, which exhibits obligate delay, the photoperiod associated with the vernal equinox decreases melatonin secretion, releasing prolactin from inhibition. Prolactin activates the corpus luteum (CL), provoking release of progesterone (P4) and other factor(s) that terminate diapause. Source: Reprinted with permission from Ref. 96.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

5. FIGURE 38. 4 Molecular markers for blastocyst dormancy and activation
FIGURE 38.4 Molecular markers for blastocyst dormancy and activation. This figure is reproduced in color in the color plate section. (A) Although normal and dormant blastocysts apparently show morphological differences, several molecular markers are regulated reversibly by the blastocyst’s state of activity. 4-OH-E2, PGE2, or cAMP can activate dormant blastocysts in vitro and either up- or downregulate specific marker molecules as indicated. Likewise, if normal blastocysts are induced to undergo dormancy by the use of delayed implantation in the uterus before the attachment reaction, expression of these markers is shifted in the reverse direction. EGFR, epidermal growth factor receptor; COX2, cyclooxygenase-2; H2R, histamine type 2 receptor; CB1, brain-type cannabinoid receptor. (B) Dormant blastocysts recovered from P4-primed delayed-implanting mice on day 7 were cultured for 24 h in Whitten’s medium, in the presence of (a) vehicle; (b) E2; or (c) 4-OH-E2. Blastocysts were processed for immunostaining and counterstained with hematoxylin. Red deposits indicate the sites of immunoreactive COX2. ICM, inner cell mass; Tr, trophectoderm. Source: Reprinted with permission from Refs 67,137.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

6. FIGURE 38.5 Signaling network for uterine receptivity and implantation. This figure is reproduced in color in the color plate section. This is a hybrid cartoon, based on mouse and human studies, portraying compartment- and cell type–specific expression of molecules and their potential functions necessary for uterine receptivity, implantation, and decidualization. Interplay of ovarian P4- and/or E2-dependent and P4- and/or E2-independent factors in the pregnant uterus in specific compartments contributes to the success of implantation in a juxtacrine– paracrine–autocrine manner. During attachment, interactions between the blastocyst and luminal epithelium (LE) involve ErbB1/4 and both transmembrane (TM) and soluble (Sol) forms of HB-EGF, as well as L-selectin ligands (sLE) expressed by the luminal epithelium to L-selectin receptors on the blastocyst. The other key signaling pathways for uterine receptivity and implantation are also shown. AA, arachidonic acid; BMP2, bone morphogenetic protein 2; cPLA2α, cytosolic phospholipase A2α; COUP-TFII, chicken ovalbumin upstream promoter transcription factor 2; Cox2, cyclooxygenase 2; E, estrogens; EC, epithelial cell (luminal and glandular epithelia); ENaC, epithelium sodium channel; ER, estrogen receptor; ErbB1/4; epidermal growth factor receptor 1/4; ERK, extracellular signal–regulated kinase; FGF, fibroblast growth factor; GE, glandular epithelium; gp130, glycoprotein 130; Hand2, heart- and neural crest derivatives–expressed protein 2; HB-EGF, heparin-binding epidermal growth factor-like growth factor; Hoxa10/11, homeobox A10/11; ICM, inner cell mass; IHH, Indian hedgehog; KLF5, Kruppel-like factor 5; LIF, leukemia inhibitory factor; LIFR, LIF receptor; LPA3, lysophosphatidic acid receptor 3; MSX1, muscle segment homeobox 1; P4, progesterone; PG, prostaglandin; PPAR-δ; peroxisome proliferator-activating receptor δ; PR, progesterone receptor; Ptc, Patched; RXR, retinoid X receptor; SC, stromal cell; SGK1, serum- and glucocorticoid-inducible kinase 1; Smo, Smoothened; STAT3, signal transducer and activator of transcription 3; Tr, trophectoderm; Wnt4/5a, Wingless-type MMTV integration site family members 4/5a. Compartment colors: blue, stroma; pink, luminal epithelium; orange, glandular epithelium; purple, epithelium at the attachment site. Source: Reprinted with permission from Ref. 153.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

7. FIGURE 38.6 HB-EGF serves as a reciprocal mediator between the luminal epithelium and activated blastocyst during attachment reaction. This figure is reproduced in color in the color plate section. (A) In situ hybridization of HB-EGF mRNA (dark-field) in the mouse uterus at 1600 h on day 4 of pregnancy. Note distinct hybridization signals in luminal epithelial cells surrounding two blastocysts in a longitudinal section. Arrows demarcate location of blastocysts. (B) Scanning electron microscopy of blastocysts co-cultured with 32D cells (a murine myeloid cell line). Zona-free day 4 (0900 h) mouse blastocysts were co-cultured with (a) parental 32D cells, (b) 32D cells displaying transmembrane form of HB-EGFTM, or (c) 32D cells synthesizing soluble form of HB-EGF for 36 h. After extensive washing to remove loosely adhering cells, blastocysts were fixed and examined by scanning electron microscopy; magnification 800×. Arrows point to 32D cells. (C) Bmp2 gene expression in response to beads preloaded with HB-EGF. Beads (7 beads/horn) preabsorbed either in BSA (control) or HB-EGF (100 ng/ml) were transferred into uterine lumens of day 4 pseudopregnant mice. Mice were killed on day 5 to examine Bmp2 expression at the sites of beads. Arrows indicate the locations of the beads. Note localized stromal expression of Bmp2 at the sites of beads preabsorbed with HB-EGF. Bar: 75 mm. Source: Reprinted with permission from Refs 9,135,220.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

8. FIGURE 38.7 Impaired oviductal embryo transport causes pregnancy loss in Cnr1−/− but not Cnr2−/− mice. This figure is reproduced in color in the color plate section. (A) Percentage of embryos recovered from oviducts or uteri in WT and Cnr1−/− mice on day four of pregnancy. (B) A representative histological section of a day 7 pregnant Cnr1−/− oviduct showing an entrapped blastocyst (Bl, arrow) at the isthmus. Mus, muscularis; S, serosa; Mu, mucosa. Bar, 100 μm. Source: Reprinted with permission from Ref. 394.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

9. FIGURE 38. 8 Defective postimplantation development in Pla2g4a–/– mice
FIGURE 38.8 Defective postimplantation development in Pla2g4a–/– mice. This figure is reproduced in color in the color plate section. (A) Representative photographs of uteri with implantation sites (blue bands) on days 5 and 6. Note very few or no implantation sites on day 5, but unevenly spaced implantation sites on day 6 in Pla2g4a–/– mice. Arrowhead and arrow indicate ovary and implantation site, respectively. Brackets indicate crowding of implantation sites. (B) Photographs of embryos isolated from implantation sites of one representative wild-type and two Pla2g4a–/– mice on day 12. Note retarded and asynchronous development of embryos in Pla2g4a–/– mice. (C) Representative photographs of conjoined embryos in a placenta (a, c) and three embryos in the same decidual envelope (b, d) from Pla2g4a–/– mice on day 12. (c) A histological section of (a) with two embryos; embryos shown in (d) are from (b). Yellow arrows indicate the source of the embryos from the decidual envelope. Source: Reprinted with permission from Ref. 47.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

10. FIGURE 38.9 Proteome profiles differ between WT and Pla2g4a–/– uteri on day 6 of pregnancy, regardless of implantation timing. This figure is reproduced in color in the color plate section. Optical images of a WT implantation site (IS) and interimplantation site (inter-IS) and Pla2g4a–/– deferred and on-time IS (upper panel). Bar, 670 μm. Ion intensity maps are shown below their respective bright-field images. Source: Reprinted with permission from Ref. 480.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition