Dissecting the role of Fgf signaling during gastrulation and left‐right axis formation in mouse embryos using chemical inhibitors

Oki, Sadaaki; Kitajima, Kenji; Meno, Chikara

doi:10.1002/dvdy.22282

Cited by 23 publications

(25 citation statements)

References 69 publications

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“…While 1 μM PD173074 recapitulates defects in early gastrula-stage Fgfr1 -/- mutants (Oki et al, 2010), we found that conceptuses exposed to this high concentration exhibited severe structural loss of tissue at the posterior embryonicextraembryonic interface, thereby precluding assessment of vascular defects there. Also, PD173074’s specificity for FGFR1 is concentrationdependent (Mohammadi et al, 1998); at 1 μM, PD173074 abrogates not only FGFR1 signaling, but also that of Vascular Endothelial Growth Factor (VEGF) (Mohammadi et al, 1998).…”

Section: Methodsmentioning

confidence: 65%

Brachyury drives formation of a distinct vascular branchpoint critical for fetal-placental arterial union in the mouse gastrula

Rodriguez

Jin

Wolfe

et al. 2017

Developmental Biology

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How the fetal-placental arterial connection is made and positioned relative to the embryonic body axis, thereby ensuring efficient and directed blood flow to and from the mother during gestation, is not known. Here we use a combination of genetics, timed pharmacological inhibition in living mouse embryos, and three-dimensional modeling to link two novel architectural features that, at present, have no status in embryological atlases. The allantoic core domain (ACD) is the extraembryonic extension of the primitive streak into the allantois, or preumbilical tissue; the vessel of confluence (VOC), situated adjacent to the ACD, is an extraembryonic vessel that marks the site of fetal-placental arterial union. We show that genesis of the fetal-placental connection involves the ACD and VOC in a series of steps, each one dependent upon the last. In the first, Brachyury (T) ensures adequate extension of the primitive streak into the allantois, which in turn designates the allantoic-yolk sac junction. Next, the streak-derived ACD organizes allantoic angioblasts to the axial junction; upon signaling from Fibroblast Growth Factor Receptor-1 (FGFR1), these endothelialize and branch, forming a sprouting VOC that unites the umbilical and omphalomesenteric arteries with the fetal dorsal aortae. Arterial union is followed by the appearance of the medial umbilical roots within the VOC, which in turn designate the correct axial placement of the lateral umbilical roots/common iliac arteries. In addition, we show that the ACD and VOC are conserved across Placentalia, including humans, underscoring their fundamental importance in mammalian biology. We conclude that T is required for correct axial positioning of the VOC via the primitive streak/ACD, while FGFR1, through its role in endothelialization and branching, further patterns it. Together, these genetic, molecular and structural elements safeguard the fetus against adverse outcomes that can result from vascular mispatterning of the fetal-placental arterial connection.

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Section: Methodsmentioning

confidence: 65%

Brachyury drives formation of a distinct vascular branchpoint critical for fetal-placental arterial union in the mouse gastrula

Rodriguez

Jin

Wolfe

et al. 2017

Developmental Biology

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“…A considerable number of studies have reported complete absence of nodal, lefty, or pitx2 expression (Field et al, 2011; Oki et al, 2010; Sakano et al, 2010; Gaio et al, 1999; Takeuchi et al, 2007; Zhang et al, 2001; Yan et al, 1999; Tsukui et al, 1999; Collignon et al, 1996; Kramer-Zucker et al, 2005; Krebs et al, 2003; Pennekamp et al, 2002), with some reporting 100% absent expression for all three genes. What does complete absence of gene expression mean?…”

Section: Discussionmentioning

confidence: 99%

“…I have also asked, is there any effect of animal model on the penetrance of LR defects? Importantly, when collecting this data, it was also apparent that many studies examine only asymmetric gene expression and use this data to make conclusions about organ position [see for example (Oki et al, 2010; Antic et al, 2010; Vick et al, 2009; Pathak et al, 2007; Houde et al, 2006; Kramer-Zucker et al, 2005; Zhang et al, 2001)]. A few studies have proposed that gene expression can be used to predict organ laterality, but the mathematical models produced to date have only been applied to extremely limited datasets (Ibanes and Izpisua Belmonte, 2009; Lohr et al, 1997; Mogi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Laterality defects are influenced by timing of treatments and animal model

Vandenberg

2012

Differentiation

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The timing of when the embryonic left-right (LR) axis is first established and the mechanisms driving this process are subjects of strong debate. While groups have focused on the role of cilia in establishing the LR axis during gastrula and neurula stages, many animals appear to orient the LR axis prior to the appearance of, or without the benefit of, motile cilia. Because of the large amount of data available in the published literature and the similarities in the type of data collected across labs, I have examined relationships between the studies that do and do not implicate cilia, the choice of animal model, the kinds of LR patterning defects observed, and the penetrance of LR phenotypes. I found that treatments affecting cilia structure and motility had a higher penetrance for both altered gene expression and improper organ placement compared to treatments that affect processes in early cleavage stage embryos. I also found differences in penetrance that could be attributed to the animal models used; the mouse is highly prone to LR randomization. Additionally, the data were examined to address whether gene expression can be used to predict randomized organ placement. Using regression analysis, gene expression was found to be predictive of organ placement in frogs, but much less so in the other animals examined. Together, these results challenge previous ideas about the conservation of LR mechanisms, with the mouse model being significantly different from fish, frogs and chick in almost every aspect examined. Additionally, this analysis indicates that there may be missing pieces in the molecular pathways that dictate how genetic information becomes organ positional information in vertebrates; these gaps will be important for future studies to identify, as LR asymmetry is not only a fundamentally fascinating aspect of development but also of considerable biomedical importance.

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“…Whole-embryo culture was performed as previously described [18]. In brief, embryos at E6.5 were collected from pregnant ICR mice and transferred to DMEM supplemented with 10% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Epiblast Ground State Is Controlled by Canonical Wnt/β-Catenin Signaling in the Postimplantation Mouse Embryo and Epiblast Stem Cells

et al. 2013

Self Cite

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Epiblast stem cells (EpiSCs) are primed pluripotent stem cells and can be derived from postimplantation mouse embryos. We now show that the absence of canonical Wnt/β-catenin signaling is essential for maintenance of the undifferentiated state in mouse EpiSCs and in the epiblast of mouse embryos. Attenuation of Wnt signaling with the small-molecule inhibitor XAV939 or deletion of the β-catenin gene blocked spontaneous differentiation of EpiSCs toward mesoderm and enhanced the expression of pluripotency factor genes, allowing propagation of EpiSCs as a homogeneous population. EpiSCs were efficiently established and propagated from single epiblast cells in the presence of both XAV939 and the Rho kinase (ROCK) inhibitor Y27632. Cell transplantation revealed that EpiSCs were able to contribute to primordial germ cells and descendants of all three germ layers in a host embryo, suggesting that they maintained pluripotency, even after prolonged culture with XAV939. Such an improvement in the homogeneity of pluripotency achieved with the use of a Wnt inhibitor should prove advantageous for manipulation of primed pluripotent stem cells.

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Dissecting the role of Fgf signaling during gastrulation and left‐right axis formation in mouse embryos using chemical inhibitors

Cited by 23 publications

References 69 publications

Brachyury drives formation of a distinct vascular branchpoint critical for fetal-placental arterial union in the mouse gastrula

Brachyury drives formation of a distinct vascular branchpoint critical for fetal-placental arterial union in the mouse gastrula

Laterality defects are influenced by timing of treatments and animal model

Epiblast Ground State Is Controlled by Canonical Wnt/β-Catenin Signaling in the Postimplantation Mouse Embryo and Epiblast Stem Cells

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