The term ‘organization centre’ was first introduced by Hans Spemann (Spemann and Mangold, 1924)
the blastopore lip of the early gastrula of the newt Triturus taeniatus had the ability to cause the formation of a full axis when transplanted onto the opposite side of a similarly staged embryo of Triturus cristatus, a different unpigmented species.
the 1924 report could discern between the host and the graft by pigment differences, which revealed the important point that the ectopic tissue developed from the host tissue.
On the nature and function of organizers Alfonso Martinez Arias* and Ben Steventon* Development. 2018 Mar 1; 145(5): dev159525. PMCID: PMC5868996
Hilde Mangold: Original microscope slides and records of the gastrula organizer experiments Wolfgang Driever a b, Jochen Holzschuh a, Luise Sommer c, Roland Nitschke b d, Angela Naumann b d, Jenny Elmer c 1, Peter Giere c Cells & Development 28 February 2024, 203909
他の動物種でも同様の実験が行われて同様の結果が得られたことから、「誘導」という概念が確立しました。
the organizer is responsible for neural induction
the organizer dorsalizes the mesoderm
Induction into the Hall of Fame: tracing the lineage of Spemann’s organizer Richard Harland Author and article information 15 OCTOBER 2008 Development (2008) 135 (20): 3321–3323.
Spemann-Mangold organizer and mesoderm induction Makoto Asashima, Yumeko Satou-Kobayashi Cells & Development Available online 1 February 2024, 203903
上の図では中胚葉が外胚葉に働きかけて神経誘導を行うことが模式的に示されています。
Introducing the Spemann-Mangold organizer: experiments and insights that generated a key concept in developmental biology Int. J. Dev. Biol. 45: 1-11 (2001) PDF
Spemann and Mangold (Spemann and Mangold, 1924) provided the initial insight showing that transplantation of dorsal lip mesoderm of the gastrulating amphibian embryo would induce an ectopic secondary axis that included a central nervous system (CNS). This led to the view that neural inducers emanate from dorsal mesoderm, a region also called Spemann’s organizer.
neural induction may start very early in development with signals mediated by the β-Catenin pathway.
Neural Induction in the Absence of Mesoderm: β-Catenin Dependent Expression of Secreted BMP Antagonists at the Blastula Stage in Xenopus Oliver Wessely,1 Eric Agius,1,2 Michael Oelgeschläger, Edgar M. Pera, and E. M. De Robertis* Dev Biol. 2001 Jun 1; 234(1): 161–173. doi: 10.1006/dbio.2001.0258 PMCID: PMC3039525 NIHMSID: NIHMS43280 PMID: 11356027
Head organizer: Cerberus and IGF cooperate in brain induction in Xenopus embryos agmur Azbazdar a, Edgar M. Pera b, Edward M. De Robertis a Cells & Development Available online 16 December 2023, 203897 Spemann later found that early dorsal blastopore lips induced heads and late organizers trunk-tail structures. Identifying region-specific organizer signals has been a driving force in the progress of animal biology. Head induction in the absence of trunk is designated archencephalic differentiation. Two specific head inducers, Cerberus and Insulin-like growth factors (IGFs), that induce archencephalic brain but not trunk-tail structures have been described previously.
Neural and Head Induction by Insulin-like Growth Factor Signals Edgar M. Pera, Oliver Wessely, Su-Yu Li, E.M. De Robertis Developmental Cell Volume 1, Issue 5, November 2001, Pages 655-665
FGF activity induces both ERNI [18,36] and Geminin (this study) in the epiblast.
Geminin binds to the chromoshadow-binding domain of Brm, displacing HP1α (Figure 4G).
the interaction of ERNI with Geminin recruits the transcriptional repressor HP1γ, thus continuing to prevent premature expression of Sox2 in the epiblast (Figure 7E).
ＦGF is required for both mesodermal [51–54] and neural induction [36,55,56]. 同じシグナルを受けて異なる分化をとげるメカニズムは、受けて側のタイミングや場所の違いによると考えられる
BERT is up-regulated within the neural plate, where it binds to both ERNI and Geminin and displaces ERNI-HP1γ complexes away from Brm, freeing the latter to activate N2 and thus Sox2 expression (Figure 9M).
We propose that BERT disrupts the interaction between Geminin and ERNI, displacing HP1γ from the N2 enhancer and thus allowing Geminin/Brahma(Brm) to induce Sox2 expression.（Ｆｉｇ．９Ｍ）
FGF signaling activates ERNI as well as Sox3 and Geminin expression in the epiblast.
A Mechanism Regulating the Onset of Sox2 Expression in the Embryonic Neural Plate 2008年 https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0060002
Molecular Biology of the CellVol. 18, No. 6ArticlesFree Access The Activity of Pax3 and Zic1 Regulates Three Distinct Cell Fates at the Neural Plate Border This is the final version – click for previous version Chang-Soo Hong, and Jean-Pierre Saint-Jeannet Marianne Bronner-Fraser, Monitoring Editor Published Online:4 Apr 2007 https://doi.org/10.1091/mbc.e06-11-1047
分子シグナリング
the neural inducers, Noggin, Chordin, and Follistatin emanate from Spemann’s organizer.3,4,5
Noggin, Chordin, and Follistatin directly bind to bone morphogenetic proteins, namely, BMP2/4/7, in the extracellular space and act as antagonists to block these BMPs from binding to the BMP receptor.6
the blockade of BMP signaling inhibits the phosphorylation of the carboxyl-terminal serine residues of the Smad1 protein, which is an intracellular mediator of the BMP signal, preventing the downstream genes of BMP signals from being activated.
the inhibition of the BMP signal induces the expression of a series of transcription factors, which in turn activate the downstream transcriptional network to further promote neural differentiation.
FGF promotes the phosphorylation of the intermediate linker domain of the Smad1 protein, instead of its carboxyl-terminal domain, and restricts the Smad1 activity.7
the combination of BMP inhibitors and FGF is essential for directing naive cells toward the neural fate.
In mouse embryos, Chordin and Noggin homologues emanate from the node, or the anterior portion of the primitive streak, and t
Chordin/Noggin double mutants exhibit severe forebrain malformation at early embryonic stages,11,12 but the development of the posterior nervous system in the Chordin/Noggin double mutant mice is relatively normal （両生類のように神経誘導すべてが抑制されるのとは事情が異なる。
哺乳類では、the anterior and posterior neural cells are already separated at the epiblast stage, and this differentiation progresses independently.13,14
The Organizer and Its Signaling in Embryonic Development Vijay Kumar,1 Soochul Park,2 Unjoo Lee,3,* and Jaebong Kim1, J Dev Biol. 2021 Dec; 9(4): 47. Published online 2021 Nov 1. PMCID: PMC8628936
Cell communication with the neural plate is required for induction of neural markersby BMP inhibition: evidence for homeogenetic induction and implications forXenopus animal cap and chick explant assays Claudia Linkera,⁎,1, Irene De Almeidaa, Costis Papanayotoua, Matthew Stowera, Virginie Sabadob,Ehsan Ghorania, Andrea Streitb, Roberto Mayora, Claudio D. Stern Developmental Biology 327 (2009) 478–486 ResearchGate
BMＰとTGF-beta signaling
Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily. BMPs were originally identified from bone matrix using an ectopic bone formation assay.
About 60 TGF-β family members have been identified so far7 with two general branches: (i) BMP/growth and differentiation factor (GDF) and (ii) the TGF-β/activin/nodal branch/mullerian-inhibiting substance or anti-mullerian hormone.8
TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation Rahman et al., Bone Res. 2015; 3: 15005. PMCID: PMC4472151
The dorsalizing and neural inducing gene follistatin is an antagonist of BMP-4 Fainsod et al., Mechanisms of Development Volume 63, Issue 1, April 1997, Pages 39-50 Mechanisms of Development https://www.sciencedirect.com/science/article/pii/S0925477397006734
The transforming growth factor-beta (TGF-β) family of cytokines, including TGF-β, bone morphogenic proteins (BMPs), and activin/inhibin, plays crucial roles in embryonic development, adult tissue homeostasis and the pathogenesis of a variety of diseases.
The highly conserved core of the canonical TGF-β/BMP signaling is a simple linear cascade that involves the TGF-β/BMP ligands, two types of receptors (type I and II) and the signal transducers, Smads.
On activation, the receptor complex phosphorylates the carboxy-terminus of receptor-regulated Smad proteins (R-Smads), including Smad1, 5 and 8 for BMP signaling and Smad2 and 3 for TGF-β signaling.
Activated R-Smads interact with the common partner Smad, Smad4, and accumulate in the nucleus, where the Smad complex directly binds defined elements on the DNA and regulates target gene expression together with numerous other factors [1–3].
Signaling cross-talk between TGF-β/BMP and other pathways Guo and Wang Cell Res. 2009 Jan; 19(1): 71–88. PMC3606489
We have identified a new member of the transforming growth factor-beta (TGF-beta) superfamily, growth/differentiation factor-10 (GDF-10), which is highly related to bone morphogenetic protein-3 (BMP-3).
Growth/differentiation factor-10: a new member of the transforming growth factor-beta superfamily related to bone morphogenetic protein-3 N S Cunningham 1, N A Jenkins, D J Gilbert, N G Copeland, A H Reddi, S J Lee Growth Factors . 1995;12(2):99-109. doi: 10.3109/08977199509028956. https://pubmed.ncbi.nlm.nih.gov/8679252/
Bone morphogenetic protein signaling: the pathway and its regulation Takuya Akiyama, Laurel A Raftery, Kristi A Wharton Author Notes Genetics, Volume 226, Issue 2, February 2024, iyad200, https://doi.org/10.1093/genetics/iyad200
BMP signaling during craniofacial development: new insights into pathological mechanisms leading to craniofacial anomalies Hiroki Ueharu and Yuji Mishina Front Physiol. 2023; 14: 1170511. 2023 May 18.
The Emerging Roles of the Cephalic Neural Crest in Brain Development and Developmental Encephalopathies Emmanuel Bruet,† Diego Amarante-Silva,† Tatiana Gorojankina, and Sophie Creuzet* Int J Mol Sci. 2023 Jun; 24(12): 9844. Published online 2023 Jun 7. doi: 10.3390/ijms24129844 PMCID: PMC10298279 PMID: 37372994
According to the most recent data, the earliest stages of neural crest induction may occur as early as gastrulation, but according to the classical model, the neural crest arises as the result of inductive actions by the adjacent non-neural ectoderm and possibly nearby mesoderm on the neural plate (Fig. 12.1). The ectodermal inductive signals are bone morphogenetic proteins (BMPs) and Wnts. Fibroblast growth factor-8 (FGF-8) from mesoderm plays a role in neural crest induction in amphibians, and it seems to be involved in mammals as well. https://basicmedicalkey.com/neural-crest/
この論文 Insights into neural crest development and evolution from genomic analysis. Simões-Costa M 1 , Bronner ME Author information Genome Research, 01 Jul 2013, 23(7):1069-1080 https://doi.org/10.1101/gr.157586.113 PMID: 23817048 PMCID: PMC3698500 のFigure 1
がわかりやすいと思います。緑色に着色された細胞が神経堤細胞（将来神経堤細胞になる細胞）です。
Distribution of fibronectin in the early phase of avian cephalic neural crest cell migration J L Duband, J P Thiery Dev Biol . 1982 Oct;93(2):308-23. doi: 10.1016/0012-1606(82)90120-8. この論文の図が『神経堤細胞』（東京大学出版会 ＵＰ ＢＩＯＬＯＧＹ）５ページ図１．３に紹介されているみたいですが、ネットで無料で見られるわけではないため論文の中身が確認できませんでした。
Neural crest precursors are born in the ectodermal epithelium constituting the tip of the neural fold. During and after the closure of the neural fold, neural crest cells emerge from the future roof plate region of the neural tube, undergoing epithelial-mesenchymal transformation. Many factors and genes, such as Pax3 (Tremblay et al., 1995), slug (Nieto et al., 1994), AP-2 (Zhang et al., 1996; Schorle et al., 1996), and Wnt-1/3a (Ikeya et al., 1997) are expressed in the dorsal most region of the neural tube, and have been shown to be involved in the generation of neural crest cells. https://journals.biologists.com/dev/article/125/15/2963/39922/Neural-crest-emigration-from-the-neural-tube
カドヘリンなどの細胞接着因子も変化するようです。
The early dorsal ectoderm expresses L-CAM (chicken E-cadherin) (Thiery et al., 1984). During neural plate invagination, the L-CAM expression is gradually replaced by that of N-cadherin (Hatta and Takeichi, 1986). At the same time, cadherin-6B (cad6B) begins to be expressed in the invaginating neural plate, most strongly at the neural crest-generating area (Nakagawa and Takeichi, 1995). In the neural tube that has just closed, N-cadherin and cad6B are co-expressed in the dorsal portion. When neural crest cells emerge from the neural tube, these cadherins become scarcely detectable, instead, cadherin-7 (cad7) appears (Nakagawa and Takeichi, 1995). https://journals.biologists.com/dev/article/125/15/2963/39922/Neural-crest-emigration-from-the-neural-tube
下の論文の説明をよく読むと、神経管が閉じた「後」とは言っていないようです。
After neural crest cells have been determined at the beginning of neurulation when the neural tube closes and pinches off from the ectoderm, they undergo an epithelial to a mesenchymal cell type change at the dorsal neural tube and transform into a migratory population that moves extensively throughout the developing embryo (Garcia-Castro and Bronner-Fraser, 1999). https://www.sciencedirect.com/science/article/pii/S0065128115000495
下の記述だとやはり神経管ができたあとで神経堤細胞ができてくるようです。
Many factors and genes, such as Pax3 (Tremblay et al., 1995), slug (Nieto et al., 1994), AP-2 (Zhang et al., 1996; Schorle et al., 1996), and Wnt-1/3a (Ikeya et al., 1997) are expressed in the dorsal most region of the neural tube, and have been shown to be involved in the generation of neural crest cells. https://journals.biologists.com/dev/article/125/15/2963/39922/Neural-crest-emigration-from-the-neural-tube
下の論文も同様。ニワトリの場合ですが、神経管完成後に神経堤細胞が出現するようです。
In the neural tube that has just closed, N-cadherin and cad6B are co-expressed in the dorsal portion. When neural crest cells emerge from the neural tube, these cadherins become scarcely detectable, instead, cadherin-7 (cad7) appears (Nakagawa and Takeichi, 1995). https://journals.biologists.com/dev/article/125/15/2963/39922/Neural-crest-emigration-from-the-neural-tube
Nonpolarized distributions of cadherin 6B and β-catenin in pre-migratory neural crest cells. Immunohistochemistry was performed on cryosections of 10-13 ss embryos for pairs of proteins in each panel. Both the open neural plate at posterior levels (A-C,G-I,M-O) and the closed neural tube at more anterior levels (D-F,J-L,P-R) were examined. Immunohistochemistry for Slug (green)/β-catenin (red) (A-F), β-catenin (green)/N-cadherin (N-cad, red) (G-L), cadherin 6B (Cad6B, green)/β-catenin (red) (M-R) were performed. The white boxed regions in C,F,I,L,M,P are magnified in C’,F’,I’,L’,M’P’, respectively. The most representative images are shown (at least three random sections per each embryo and at least seven embryos were analyzed). Scale bar: 25 μm. 15 August 2010 Cadherin 6B induces BMP signaling and de-epithelialization during the epithelial mesenchymal transition of the neural crest Ki-Sook Park, Barry M. Gumbiner Author and article information Development (2010) 137 (16): 2691–2701. https://journals.biologists.com/dev/article/137/16/2691/43888/Cadherin-6B-induces-BMP-signaling-and-de
Fig. 2. Organismal differences in NCC EMT. The process of NCC EMT varies based on the organism as well as at different axial levels. In avian species, NCCs must delaminate from the neural tube before emigrating (Monroy et al., 2022). In other species, such as zebrafish (Rajan et al., 2018; Wang et al., 2019) and frogs (Lee and Saint-Jeannet, 2011), NCCs arise adjacent to the neural tube before emigrating laterally. Mouse NCCs lack collective migration and instead quickly mesenchymalize for individual migration before the neural tube has closed (Lee et al., 2013). Human cells appear to migrate similarly to both rodents and avians (Betters et al., 2010). Figure created using BioRender.com.
Time to go: neural crest cell epithelial-to-mesenchymal transition July 2022Development 149(15) DOI: 10.1242/dev.200712 LicenseCC BY 4.0 https://www.researchgate.net/publication/362358835_Time_to_go_neural_crest_cell_epithelial-to-mesenchymal_transition/citations
Analysis of early human neural crest development Developmental Biology Volume 344, Issue 2, 15 August 2010, Pages 578-592ヒト胚で神経堤細胞分子マーカーの局在を調べた論文
the process of a material breaking or being broken into thin layers, or an example of this https://dictionary.cambridge.org/dictionary/english/delamination
An important feature of NCC development is their delamination from the neuroepithelium via EMT, following which NCC migrate throughout the embryo and undergo differentiation.
Identification and characterization of intermediate states in mammalian neural crest cell epithelial to mesenchymal transition and delamination https://doi.org/10.7554/eLife.92844.2
Neural crest emigration from the neural tube depends on regulated cadherin expression Shinichi Nakagawa, Masatoshi Takeichi Author and article information Development (1998) 125 (15): 2963–2971. https://doi.org/10.1242/dev.125.15.2963 https://journals.biologists.com/dev/article/125/15/2963/39922/Neural-crest-emigration-from-the-neural-tube
Jean Paul Thiery, Hervé Acloque, Ruby Y.J. Huang, M. Angela Nieto, Epithelial-Mesenchymal Transitions in Development and Disease, Cell, Volume 139, Issue 5, 2009, Pages 871-890, ISSN 0092-8674,
四肢の形成と上皮-間充織相互作用
The apical ectodermal ridge (AER) maintains the mesenchyme in a proliferating state (preventing it from form cartilage) that enables the linear growth of the limb; maintains the expression of those molecules that generate the anterior-posterior axis; interacts with the proteins specifying the anterior-posterior and dorsal-ventral axis. AER formation requires bone morphogenetic protein (BMP) signaling and can be prevented in transgenic mice by expressing a dominant negative BMP receptor under the control of an epidermis-specific promoter. The signal for limb bud formation comes from mesodermal cells, which secrete FGF-10, capable of initiating interactions between the ectoderm and mesoderm (Xu et al., 1998, Yonei-Tamura et al.,1999). FGF-10 induces the overlying ectoderm to form the AER.
Moreover, FGF-10 induces the AER to synthesize and secrete FGF-8, which stimulates mitosis in the mesenchymal cells. The FGF-10 knockout mouse forms no limb buds.
Int. J. Dev. Biol. 58: 303 – 306 (2014) https://doi.org/10.1387/ijdb.140143dr Vol 58, Issue 5 Epithelial-mesenchymal interactions: a fundamental Developmental Biology mechanism Essay | Published: 30 September 2014 Domenico Ribatti* and Marcello Santoiemma
Limbs emerge from the body flank as a consequence of localized epithelial–mesenchymal interactions that result in rapid proliferation of mesenchymal cells leading to the formation of limb buds. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/lateral-plate-mesoderm
The lateral plate mesoderm Karin D. Prummel,1,2,* Susan Nieuwenhuize,1,2,* and Christian Mosimann1,2,‡ Development. 2020 Jun 15; 147(12): dev175059. Published online 2020 Jun 19. doi: 10.1242/dev.175059 PMCID: PMC7328003
Face Development in the Womb – Inside the Human Body: Creation – BBC BBC チャンネル登録者数 1450万人
顔の発生に関する講義動画
下の動画は、発生途上のどの構造が顔のどの部分になるかがわかりやすく説明されていました。
Development of the Face and Palate 浸透 チャンネル登録者数 335万人 （１：４９〜から鰓弓の話）
上の動画にでてきた「部位」の名称や説明をざっとまとめておきます。
primitive pharynx
branchial arches (pharyngeal arches)
ectomesenchyme: neural crest cells from rhombomeres 1 and migrate to and infiltrate into the mesodermal tissues in the brahcial arches to make ectomesenchyme
branchial grooves：外側からみたときの鰓弓と鰓弓の間のくぼんだ部分
pharyngeal pouches：内側からみたときの鰓弓と鰓弓の間のくぼんだ部分
maxillary process: branchial arch I が２つに分かれたうちの一つ（前方側）。
Duplicated zebrafish co-orthologs of parathyroid hormone-related peptide (PTHrP, Pthlh) play different roles in craniofacial skeletogenesis Yi-Lin Yan, Poulomi Bhattacharya,1 Xin Jun He, Bhaskar Ponugoti,1 Ben Marquardt,1 Jason Layman,1 Melissa Grunloh,1 John H. Postlethwait, and David A. Rubin1 J Endocrinol. 2012 Sep; 214(3): 421–435. Published online 2012 Jul 3. doi: 10.1530/JOE-12-0110 PMCID: PMC3718479 NIHMSID: NIHMS488120 PMID: 22761277 Parathyroid hormone (PTH) acts as the main hypercalcemic hormone while PTH-related protein (PTHrP, official human symbol PTHLH (PTH-like hormone) and referred to as Pthlh in this manuscript), is essential for embryonic development, differentiation, and tissue patterning (Philbrick et al. 1996). Unregulated paracrine secretion of Pthlh is associated with a type of tumor that results in elevated blood calcium levels, a condition called humoral hypercalcemia of malignancy (HHM), while regulated secretion of Pthlh during mouse embryogenesis is essential for the developmental patterning of cartilage, bone, teeth, CNS, pancreas, and other tissues (Karperien et al. 1996, Philbrick et al. 1996, Clemens et al. 2001).
“Owing to” and “due to” are often used interchangeably in casual language, but there is a subtle difference in their usage:
“Owing to” typically implies a more direct or immediate cause, and it is often used to introduce the reason for something.
“Due to” is a bit more general and can be used to indicate a cause, but it can also denote an explanation or attribution of something.
For example:
“The cancellation of the event was owing to the bad weather.” (The bad weather directly caused the cancellation.) キャンセルの原因は悪天候でした。
“The delay was due to unforeseen circumstances.” (Unforeseen circumstances were the cause, but it might not be as direct as in the first example.) 何らかの理由で遅延が生じました。
In some contexts, they can be used interchangeably without much difference in meaning. However, in formal writing or contexts where precision is necessary, it’s best to use them according to their nuances.
