カールソンの教科書のFIG 4.17に、栄養膜 Trophoblastと内部細胞塊の運命決定のメカニズムが説明されていました。栄養膜細胞ではHippoシグナリングが抑制された結果Yapが活性化された状態で核に移行し転写因子として、核内に存在するもう一つの転写因子Tead4と協同して、Cdx2遺伝子の発現を誘導します。Cdx2遺伝子産物は、Oct4やNanogの遺伝子発現を抑制します。一方、内部細胞塊の細胞内ではHippoシグナルが活性された結果Yapのセリン残基をリン酸化することによりYapは抑制されます。Cdx2遺伝子の発現が抑制された状態では、Oct-4、Nanog、Sox-2といった遺伝子が発現されて、細胞は内部細胞塊の運命をたどります。
さらに内部細胞塊の細胞は、FGF4を分泌し、FGF4はオートクリン、パラクリンとして作用します。オートクリン作用としては内部細胞塊の細胞自身に作用し、パラクリンの作用としては栄養膜細胞に働きかけます。
さて、内部細胞塊が分泌するFGF-4はオートクリン、パラクリンとして作用することにより、どのような役割を果たしているのでしょうか。Claude.aiに訊いてみました。
質問：What is the role of FGF-4 in the maintenance of inner cell mass fate and trophoblaast cell fate?
回答：
FGF-4 (Fibroblast Growth Factor 4) plays a crucial role in the early development of mammalian embryos, particularly in the maintenance and differentiation of the inner cell mass (ICM) and trophoblast lineages. Here’s an overview of its role in these processes:
1. Inner Cell Mass (ICM) fate:
FGF-4 is primarily produced by the cells of the inner cell mass. Its role in maintaining ICM fate includes:
a) Supporting ICM proliferation: FGF-4 acts as a mitogen, promoting cell division and growth of ICM cells.
b) Maintaining pluripotency: FGF-4 signaling helps maintain the expression of key pluripotency factors like Oct4 and Nanog in the ICM.
c) Preventing premature differentiation: FGF-4 signaling inhibits the differentiation of ICM cells into primitive endoderm, helping to maintain the epiblast population.
2. Trophoblast cell fate:
While FGF-4 is produced by the ICM, it acts primarily on the trophoblast lineage. Its role in trophoblast fate includes:
a) Promoting trophoblast proliferation: FGF-4 stimulates the proliferation of trophoblast cells, which is crucial for the expansion of the trophectoderm.
b) Maintaining trophoblast stem cell population: FGF-4 signaling is essential for the maintenance of trophoblast stem cells, preventing their premature differentiation.
c) Regulating trophoblast differentiation: FGF-4 helps regulate the balance between trophoblast stem cell self-renewal and differentiation into specialized trophoblast cell types.
d) Paracrine signaling: The production of FGF-4 by the ICM and its action on trophoblast cells establishes an important paracrine signaling axis between these two lineages.
The interaction between FGF-4 and its receptor FGFR2 is particularly important for these processes. The ICM expresses FGF-4, while the trophectoderm expresses FGFR2, allowing for this paracrine signaling to occur.
It’s worth noting that the complete absence of FGF-4 signaling leads to peri-implantation lethality in mouse embryos, highlighting its critical role in early embryonic development and the maintenance of both ICM and trophoblast lineages.
Would you like me to elaborate on any specific aspect of FGF-4’s role in these processes?
Claude.aiはネットの情報をまとめているだけなので必ずしも原著論文に裏付けられたものとは限りません。原著論文を教えてもらえないか聞いてみました。
質問：For each of your statement, could you please show the reference (original scientific papers)?
回答するけど正しさは保証できないから自分でチェックしててという前置きとともに回答してくれました。
回答：
Certainly, I’d be happy to provide references for each statement. However, I want to preface this by saying that as an AI, I don’t have direct access to a database of scientific papers. While I strive for accuracy, there’s a possibility that I might inadvertently provide incorrect citations. I recommend double-checking these references to ensure their accuracy. With that said, here are the statements with potential references:
- Inner Cell Mass (ICM) fate:
a) Supporting ICM proliferation: Tanaka, S., Kunath, T., Hadjantonakis, A. K., Nagy, A., & Rossant, J. (1998). Promotion of trophoblast stem cell proliferation by FGF4. Science, 282(5396), 2072-2075. https://www.science.org/doi/10.1126/science.282.5396.2072 Abastracより “A culture of mouse blastocysts or early postimplantation trophoblasts in the presence of fibroblast growth factor 4 (FGF4) permitted the isolation of permanent trophoblast stem cell lines. These cell lines differentiated to other trophoblast subtypes in vitro in the absence of FGF4 and exclusively contributed to the trophoblast lineage in vivo in chimeras.”
b) Maintaining pluripotency: Kunath, T., Saba-El-Leil, M. K., Almousailleakh, M., Wray, J., Meloche, S., & Smith, A. (2007). FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development, 134(16), 2895-2902. “Here, we delineate the role of autocrine production of fibroblast growth factor 4 (Fgf4) and associated activation of the Erk1/2 (Mapk3/1) signalling cascade. ‥ The key downstream role of Erk signalling is revealed by examination of Erk2-null ES cells,which fail to undergo either neural or mesodermal differentiation in adherent culture, and retain expression of pluripotency markers Oct4, Nanog and Rex1. “
c) Preventing premature differentiation: Yamanaka, Y., Lanner, F., & Rossant, J. (2010). FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development, 137(5), 715-724. Abstractより ”Primitive endoderm (PE) and epiblast (EPI) are two lineages derived from the inner cell mass (ICM) of the E3.5 blastocyst. Recent studies showed that EPI and PE progenitors expressing the lineage-specific transcriptional factors Nanog and Gata6, respectively, arise progressively as the ICM develops. ‥ we propose a model in which stochastic and progressive specification of EPI and PE lineages occurs during maturation of the blastocyst in an FGF/MAP kinase signal-dependent manner.”
- Trophoblast cell fate:
a) Promoting trophoblast proliferation: Tanaka, S., Kunath, T., Hadjantonakis, A. K., Nagy, A., & Rossant, J. (1998). Promotion of trophoblast stem cell proliferation by FGF4. Science, 282(5396), 2072-2075.
b) Maintaining trophoblast stem cell population: Nichols, J., Zevnik, B., Anastassiadis, K., Niwa, H., Klewe-Nebenius, D., Chambers, I., … & Smith, A. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell, 95(3), 379-391. Abstractより ”Oct4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent. Instead, they are restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation is not maintained in Oct4−/− embryos. Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm.”
c) Regulating trophoblast differentiation: Simmons, D. G., & Cross, J. C. (2005). Determinants of trophoblast lineage and cell subtype specification in the mouse placenta. Developmental Biology, 284(1), 12-24. 総説論文
d) Paracrine signaling: Chai, N., Patel, Y., Jacobson, K., McMahon, J., McMahon, A., & Rappolee, D. A. (1998). FGF is an essential regulator of the fifth cell division in preimplantation mouse embryos. Developmental Biology, 198(1), 105-115. Abstractより “FGF signaling induces the cell division of embryonic and extraembryonic cells in the preimplantation mouse embryo starting at the fifth cell division. The signal requirement for FGF is cell autonomous, but is not required to prevent cell death. This provides the first evidence for the necessity of a growth factor before implantation.”
Regarding the importance of FGF-4 and FGFR2 interaction: Arman, E., Haffner-Krausz, R., Chen, Y., Heath, J. K., & Lonai, P. (1998). Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. Proceedings of the National Academy of Sciences, 95(9), 5082-5087. Abstractより ”Preimplantation development was normal until the blastocyst stage. Homozygous mutant embryos died a few hours after implantation”
For the statement about FGF-4 absence leading to peri-implantation lethality: Feldman, B., Poueymirou, W., Papaioannou, V. E., DeChiara, T. M., & Goldfarb, M. (1995). Requirement of FGF-4 for postimplantation mouse development. Science, 267(5195), 246-249. Abstractより ”Embryos homozygous for the null allele underwent uterine implantation and induced uterine decidualization but did not develop substantially thereafter. As was consistent with their behavior in vivo, Fgf4 null embryos cultured in vitro displayed severely impaired proliferation of the inner cell mass, whereas growth and differentiation of the inner cell mass were rescued when null embryos were cultured in the presence of FGF-4 protein.”
Again, I want to emphasize that these citations should be verified for accuracy. If you need more specific or recent references, I would recommend conducting a literature search using scientific databases.