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WIREs Dev Biol
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The mouse fetal‐placental arterial connection: A paradigm involving the primitive streak and visceral endoderm with implications for human development

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Abstract In Placentalia, the fetus depends upon an organized vascular connection with its mother for survival and development. Yet, this connection was, until recently, obscure. Here, we summarize how two unrelated tissues, the primitive streak, or body axis, and extraembryonic visceral endoderm collaborate to create and organize the fetal‐placental arterial connection in the mouse gastrula. The primitive streak reaches into the extraembryonic space, where it marks the site of arterial union and creates a progenitor cell pool. Through contact with the streak, associated visceral endoderm undergoes an epithelial‐to‐mesenchymal transition, contributing extraembryonic mesoderm to the placental arterial vasculature, and to the allantois, or pre‐umbilical tissue. In addition, visceral endoderm bifurcates into the allantois where, with the primitive streak, it organizes the nascent umbilical artery and promotes allantoic elongation to the chorion, the site of fetal‐maternal exchange. Brachyury mediates streak extension and vascular patterning, while Hedgehog is involved in visceral endoderm's conversion to mesoderm. A unique CASPASE‐3‐positive cell separates streak‐ and non‐streak‐associated domains in visceral endoderm. Based on these new insights at the posterior embryonic‐extraembryonic interface, we conclude by asking whether so‐called primordial germ cells are truly antecedents to the germ line that segregate within the allantois, or whether they are placental progenitor cells. Incorporating these new working hypotheses into mutational analyses in which the placentae are affected will aid understanding a spectrum of disorders, including orphan diseases, which often include abnormalities of the umbilical cord, yolk sac, and hindgut, whose developmental relationship to each other has, until now, been poorly understood. This article is categorized under: Birth Defects > Associated with Preimplantation and Gastrulation Early Embryonic Development > Gastrulation and Neurulation
Primitive streak and visceral endoderm: historic view. (a, b) Axial midline, embryonic region of the mouse egg cylinder (~E7.25). (a) A three‐dimensional schematic drawing of the embryonic portion of the egg cylinder. (b) Sagittal view of the mouse egg cylinder cut at the level of the dotted line in (a). 1, 2: the primitive streak is extending anteriorly through the midline; 3, node; 4, head process/notochord along ventral midline. (c‐e) Extraembryonic endoderm. Schematic diagrams of sagittal sections through the mouse conceptus. (c) Primitive endoderm of the blastocyst expands to become the parietal and visceral endoderm of the egg cylinder (d, e). Anterior visceral endoderm (d) and extraembryonic visceral endoderm of the yolk sac (e) have inducing properties. See text for details
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Formation and remodeling of the extraembryonic arterial vessels. Schematic diagrams showing the formation and remodeling of the umbilical and omphalomesenteric arteries at the posterior embryonic‐extraembryonic interface in the mouse gastrula. (a–c), (e), sagittal views; (d), frontal view. Distal‐proximal coordinates on the compass refer to the spatial regions of the allantois without reference to the whole conceptus. See text for details with the following notes: (a–c) the horizontal dotted line separates the extraembryonic (X) and embryonic (E) regions, according to Lawson et al. (). (b–i) The vessel of confluence is red and reinforced by a white asterisk. (b) The vertical blue dotted line indicates angioblasts of the left dorsal aorta making their way toward the vessel of confluence (those of the right dorsal aorta are not visible in sagittal view). (d) Both left and right dorsal aortae, now endothelialized, are coalescing into a single unbranched segment just beneath the vessel of confluence (asterisk); the visceral yolk sac has been reflected and is not visible. (f) Scanning electron micrograph colorized in this review to show the disposition of the three major arterial vessels (left dorsal aorta, blue) and their connection to the vessel of confluence, ~E9.5. Reprinted with permission from Gest and Carron (). Copyright 2003, Wiley. (g–i) Series of schematic diagrams showing remodeling of the medial umbilical roots (g, h) and the appearance of the lateral umbilical roots (h, i) on either side of the remodeled medial roots. al, allantois; am, amnion; bi, yolk sac blood island; ch, chorion; da, dorsal aortae; E, embryonic; hg, hindgut; lur, lateral umbilical roots; mur, medial umbilical roots; oa, omphalomesenteric artery; ps, primitive streak; ua, umbilical artery; uv, umbilical vein; X, extraembryonic; xve, extraembryonic visceral endoderm of the visceral yolk sac
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The yolk sac and pre‐umbilical cord of mouse and humans. In all panels, anterior is to the left, and posterior is to the right. (a) Parietal yolk sac (pys), mouse. Mouse conceptus dissected from maternal deciduum shows outer layers of trophectoderm and parietal endoderm, which together form the PYS. The red color is maternal red blood cells closely associated with the trophectoderm. (b) Mouse conceptus after reflection of the parietal yolk sac, revealing the visceral yolk sac (vys). The boxed region indicates the fetal‐placental connection. (c) Mouse embryo and its connection to the pre‐umbilical cord. The VYS has been reflected to expose the mouse embryo and its connection to the allantois (boxed region). Scale bar, 0.5 mm. (d) Schematic diagram of the conceptus in (a), sagittal slice, revealing discrete tissues and their relationship to each other. Boxed region, fetal‐placental connection; see text for details. (e) Human embryo and connection to yolk sac and pre‐umbilical cord. The surrounding chorion has been reflected to expose the embryo and its relationship to the secondary yolk sac (ys) and pre‐umbilical cord (bs, body stalk; see text for explanation). Boxed region, fetal‐placental connection; see text for details. Scale bar, 0.5 mm. Image downloaded from the Digitally Reproduced Embryonic Morphology database (http://virtualhumanembryo.lsuhsc.edu/DREM/OnlineDisks.html). (f) Schematic diagram of the human conceptus in (e), sagittal slice, revealing discrete tissues, and their relationship to each other. Boxed region, fetal‐placental connection. Panels (a–c) are reprinted with permission from Pereira et al. () with creative commons license (CC by 2.0). ac, amniotic cavity; al, allantois; am, amnion; bs, body stalk; ch, chorion; em, embryo; epc, ectoplacental cone; epv, ectoplacental cavity; mb, maternal blood; pys, parietal yolk sac (mouse); vys, visceral yolk sac (mouse); xc, exocoelomic cavity; yc, yolk cavity; ys, secondary yolk sac (human). The key indicates general categories of germ layers, without reference to embryonic or extraembryonic
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Humans and mice share conserved features at the posterior embryonic‐extraembryonic interface. (a–c) Schematic diagrams depicting the shared region of hypoblast/visceral endoderm at the posterior embryonic‐extraembryonic interface in humans, (a) and in mice (b, c). In (b), the mouse egg cylinder has been spliced down the center of extraembryonic ectoderm (dotted vertical line) and splayed open (curved arrows) to show the similar topographical relationship (c) between the AX (red square in both species) and the posterior embryonic‐extraembryonic junction in both species. Reprinted with permission from Rodriguez and Downs (). Copyright 2017, Elsevier. (d, e) Histological sections of the posterior region of human (Carnegie Stage 7), (d) and mouse (4 s, ~E8.25), (e) showing the conserved dense core (dotted white line surrounding white asterisk) and the vessel of confluence (boxed regions, enlarged in insets, black asterisk indicates the VOC lumen). Reprinted with permission from Rodriguez et al. (). Copyright 2017 Elsevier. al, allantois; am, amnion; cs, connecting stalk, or yolk sac diverticulum; em, embryo; xc, exocoelomic cavity; yc, yolk cavity; ys, visceral yolk sac (mice), secondary yolk sac (humans). See Rodriguez et al. () and Rodriguez and Downs () for details on the association of the dense core and vessel of confluence with extraembryonic endoderm in both species
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The allantoic rod. (a, b) Comparison of the allantoic core domain and embryonic node when a drop of lipophilic dye was introduced into both structures. (a) Frontal (posterior) view of the site of initial labeling (white asterisk) in the ACD; labeled cells remain in place and form a midline file extending further posteriorly through the allantois. The white arrowhead indicates the embryonic‐extraembryonic junction. Reprinted with permission from Downs et al. (). Copyright 2009, Elsevier. (b) Frontal (anterior) view of the initial site of labeling in the node (n, white arrow); labeled cells both remain in place and form a midline file further anteriorly, contributing to the notochord (ntc, white arrowhead). Reprinted with permission from Beddington (). Copyright 1994, Development. (c–e) Allantoic rod, defined by COLLAGEN IV (COLIV, brown color, c) in a sagittally oriented histological section; (d, e) three‐dimensional reconstructions from histological sections to show the relationship between the ACD and COLIV‐positive rod (d), and between the ACD, allantoic rod, and umbilical artery (e). Reprinted with permission from Rodriguez and Downs (). Copyright 2017, Elsevier. The compass within panel (a) indicates the distal‐proximal coordinates of the allantois relative to its position within the exocoelom, and the anterior–posterior coordinates of the allantoic core domain relative to the embryonic primitive streak in (a), (c–e). al, allantois, ACD, allantoic core domain; al rod, allantoic rod; AX, allantois‐associated extraembryonic visceral endoderm; COLIV, COLLAGEN TYPE IV protein; hg, hindgut; n, node; ntc, notochord; oa, omphalomesenteric artery; ua, umbilical artery; VOC, vessel of confluence; vys, visceral yolk sac
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Comparison of the chorionic disks of human and mouse. In humans and mice, the mature chorio‐allantoic placenta is composed of the umbilical cord and the multilayered chorionic disk. The fetal villi of the human form the fetal placenta, while they are part of the chorionic labyrinth in the mouse (Georgiades, Ferguson‐Smith, & Burton, ). Note that the maternal spiral arteries in both species enter the chorionic disk in perfect alignment with the umbilical cord's central insertion onto the disk; though not visible here, the umbilical artery is connected at its fetal end to the omphalomesenteric artery and fetal dorsal aortae, all of which are patterned with respect to the primitive streak. Thus, the entire fetal‐placental arterial connection appears to be patterned with respect to the primitive streak. See text for details. Reprinted with permission from Krishnan, McComb, and Nguyen (). Copyright 2013, Elsevier. Other notes: the green color in the mouse placenta, right, indicates the single layer of trophoblast giant cells which form a border between the mouse chorionic disk and maternal deciduum, and the underlying layer of trophectoderm‐derived spongiotrophoblast
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Variation in chorio‐allantoic and chorio‐vitelline placentae among select Placentalia. Species: 1, Human; 2, Equine; 3, Feline; 4, Rodent; 5, Ruminant; 6, Swine. Extraembryonic tissues: Am, amnion; Al, allantois (colored light blue); V, yolk sac (“vitelline tissue”, colored red); C, chorion. Though not explicitly shown, the umbilical (allantoic) artery, omphalomesenteric (vitelline/yolk sac) artery, and fetal dorsal aortae are patent within the base of the allantois/umbilical cord. Reprinted with permission from Fernandes et al. () with creative commons license (CC by 4.0)
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The fetal‐placental arterial connection in Sirenomelia. Schematic illustration of the umbilical vessels and aorta in a normal fetus (a) and in one with sirenomelia (b). In normal fetuses, two umbilical arteries connect the fetus with its placenta with each umbilical artery coming off one of the common iliac arteries that divides the aortic flow into the hindlimb. In fetuses with sirenomelia, a single umbilical artery (SUA), which abnormally comes off the abdominal aorta, forges the fetal‐placental arterial connection. Reprinted with permission from Garrido‐Allepuz, Gonzalez‐Lamuno, and Ros () with creative commons license (CC by‐NC‐SA 3.0)
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The AX becomes the hindgut lip, a progenitor pool for the fetal‐placental interface. (a) Just prior to turning, the AX is transformed into the hindgut lip (hgl), the latter of which continues to exfoliate cells that contribute to structures at the allantoic‐yolk sac junction. Reprinted with permission from Rodriguez and Downs (). Copyright 2017, Elsevier. (b) As the embryo undergoes turning to acquire the fetal position, the arterial connection is remodeled into the medial umbilical roots (mur). Reprinted with permission from Rodriguez et al. (). Copyright 2017, Elsevier. (c) During the fetal period, the medial umbilical roots regress as the lateral umbilical roots (lur) sprout from the aorta to connect with the umbilical artery at the VOC's arterial branchpoint. Reprinted with permission from Rodriguez et al. (). Copyright 2017, Elsevier. ACD, allantoic core domain; al, allantois; am, amnion; cd, chorionic disk; da, dorsal aorta; hg, hindgut; hgl, hindgut lip; lur, lateral umbilical roots; mur, medial umbilical roots; oa, omphalomesenteric artery; ua, umbilical artery; vys, visceral yolk sac; vv, vitelline vessels; xve, extraembryonic visceral endoderm
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Fate and potency of the headfold‐stage allantois (~E7.75–E8.0). (a) Fate. (b) Potency. The fate and potency of the allantois were determined by synchronous orthotopic (fate) and synchronous heterotopic (potency) grafting of groups of cells from a donor conceptus into a host conceptus, followed by whole embryo culture, appropriate staining for grafted cells, and histology (Downs & Harmann, ; Mikedis & Downs, ). Four regions of the allantois were fate‐mapped (Downs & Harmann, ; Mikedis & Downs, ) (a); of these, only three have been potency‐mapped (Downs & Harmann, ) (b). This is because at the time of potency mapping, we took the base of the allantois to be the region above the imaginary dotted line that extends from the site of insertion of the allantois into the amnion and visceral yolk sac, and which is now defined by the distal ACD (dACD), omitting the proximal ACD (pACD) beneath it. The headfold‐stage embryonic posterior primitive streak had previously been fate‐mapped by a similar grafting method (Tam & Beddington, ), and was used as in internal control in the fate and potency experiments of the allantois. Note: In Mikedis and Downs (), the mid‐allantoic region and dACD were combined. See text for further details. The compass refers to the distal‐proximal regions of the allantois relative to its position in the exocoelom. al, allantois; am, amnion; em, embryo; vys, visceral yolk sac
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Extension of the primitive streak into the exocoelom and expansion into the allantoic core domain (ACD): current view. (a–d) Schematic diagrams showing sequential extension of the posterior end of the primitive streak into the exocoelom (a), followed by formation of the allantoic bud (b), the streak's expansion into the allantoic core domain (c), and ACD regression (d), all of which were observed by immunostaining for BRACHYURY, and by electron microscopy (Downs et al., ). Other notes: (a), The Brachyury (T) genotypes show failure of the streak to fully extend with one (TC/T+) or no (TC/TC) normal copies of T. (b) The small cluster of red circles indicates the hemangioblasts of the prospective vessel of confluence. (c) The dotted line surrounding the nascent vessel of confluence indicates that the latter has not yet fully endothelialized. (a–d) The arrow shows the progressive anterior translocation of the allantoic‐yolk sac junction toward the embryo. (e–g) Identification of the posterior extension of the primitive streak at the headfold stages (~E7.75–E8.0) by BRACHYURY protein (e), reprinted with permission from Inman and Downs (). Copyright 2006, Elsevier, and mRNA (f, g; light and dark field images, respectively), reprinted with permission from Woda et al. (), creative commons license (CC by 4.0). See text for further details. ac, amniotic cavity; ACD, allantoic core domain; al, allantois; am, amnion; AX, allantois‐associated extraembryonic visceral endoderm; bi, blood island; ch, chorion; dAX, distal [to] allantois‐associated extraembryonic visceral endoderm; hg, hindgut; hgl, hindgut lip; m, embryonic mesoderm; n, node; ntc, notochord; pbi, prospective blood island; ps, primitive streak; vv, vitelline vessel; xc, exocoelomic cavity; xve, extraembryonic visceral endoderm. The compass to the left of panel (a) indicates the distal‐proximal coordinates of the allantois relative to its position within the exocoelom, and the anterior–posterior coordinates of the allantoic core domain relative to the embryonic primitive streak
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Whole embryo culture of mouse post‐implantation conceptuses using the method of K. Lawson and colleagues. (a) Freshly dissected examples of pre‐ and early‐streak stage conceptuses (~E6.5–E6.75) prior to whole embryo culture. (b) Example of embryo development and chorio‐allantoic placentation after 48 hr in whole embryo culture. The chorio‐vitelline placenta (cvp) has been reflected to show that the allantois has elongated and fused with the chorion. al, allantois; am, amnion; ch, chorion; cvp, chorio‐vitelline placenta; 9 s, 9 somite pairs. K. Downs, unpublished
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Anterior and posterior extension of the antero‐posterior axis. A drop of DiI was simultaneously introduced into the node (n) and allantoic core domain (white asterisk) of a headfold‐stage (~E7.75–E8.0) conceptus. After whole embryo culture, the visceral yolk sac was removed, the amnion was pierced, and the embryo was flattened beneath a coverslip and photographed, as previously described (Downs et al., ). Anteriorly, DiI has remained in the node and labeled descendant cells have contributed to the notochord (ntc), as previously described (Beddington, ). The notochordal plate (np), negative for DiI, was formed by unlabeled non‐axial contributions (Yamanaka, Tamplin, Beckers, Gossler, & Rossant, ) and thus, was not labeled. Posteriorly, the DiI has remained in the ACD (asterisk), with labeled descendants forming a linear file through the midline, extending the axial midline further posteriorly. The compass refers to the anterior‐posterior coordinates along the length of the axial midline. Scale bar, 200 μm. K. Downs, unpublished data. al, allantois; hf, headfold; hp, head process; n, node; ntc, notochord; pps, embryonic posterior primitive streak
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The allantoic core domain and extraembryonic visceral endoderm interact to create and organize the fetal‐placental connection. (a, b) Schematic diagrams through the sagittal midline of the mouse gastrula (headfold stages, ~E7.75–E8.0) showing the relevant region (dotted box, (a), enlarged in (b)) that builds the fetal‐placental connection, highlighting the relatively low and high levels of Ptch1 in the axial extraembryonic visceral endoderm. (c) Relative levels of Ptch1 in axial extraembryonic visceral endoderm, and absence of detectable Ptch1 in blood island‐associated visceral endoderm in a representative histological section (2 s stage), just oblique to the sagittal orientation. Dotted horizontal line indicates embryonic/extraembryonic border, as in Figure . Reprinted with permission from Rodriguez and Downs (). Copyright 2017, Elsevier. (d–g) Sequential steps in creation and organization of the fetal placental connection. See text for further details. Other notes: (e–g) The single arrow indicates translocation of the allantoic‐yolk sac junction toward the embryo. (f, g) The double arrow indicates Hedgehog‐mediated liberation of AX‐derived mesoderm to shape the allantois and create distinct arterial vessels. Reprinted with permission from Rodriguez and Downs (). Copyright 2017, Elsevier. ac, amniotic cavity; ACD, allantoic core domain; al, allantois; am, amnion; AX, allantois‐associated extraembryonic visceral endoderm; bi, blood island; CASP3, activated CASPASE‐3 protein; ch, chorion; dAX, distal [to] allantois‐associated extraembryonic visceral endoderm; epv, ectoplacental cavity; pbi, prospective blood island; ps, primitive streak; vys, visceral yolk sac; xc, exocoelom; xve, extraembryonic visceral endoderm
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