原腸胚形成
原腸胚形成（Gastrulation）是大部分動物胚胎發育中都會經歷的一個階段。在本階段中，只有一層細胞的囊胚會發生重組，形成一個含有三個胚層（即外胚層（ectoderm）、中胚層（mesoderm）、內胚層（endoderm））細胞的原腸胚（gastrula）[1][2]。
| 原腸胚形成 | |
|---|---|
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| 標識字符 | |
| MeSH | D054262 |
| 格雷氏 | p.47 |
| 《解剖學術語》 [在維基數據上編輯] | |
原腸胚形成發生於卵裂之後，原腸胚形成完成後，胚胎進入原腸胚時期，開始器官發生過程。新形成的三個胚層的細胞會組合並發育為器官[3]。每一個胚層的細胞都能發育為特定的器官和組織。外胚層會發育為表皮、神經嵴，以及之後會發育為神經系統的組織。中胚層細胞位於外胚層細胞和內胚層細胞之間，能發育為體節，生成肌肉，以及屬於肋骨、椎骨的軟骨。另外，中胚層還能發育為真皮、脊髓、血管與血液、骨，以及結締組織。內胚層細胞則會發育為消化系統和呼吸系統的上皮，比如肝和胰腺[4]。原腸胚形成過程結束後，機體的細胞都會組織為被上皮等締合的細胞包圍的群體，或者像間充質那樣分散在各處[2][5]。
原腸胚形成的分子機制以及所需時間在不同的生物中是不同的。不過，不同生物之間的原腸胚形成仍然有一些共同點，如：一，胚胎的拓撲結構會發生變化，從單連通的表面（類似於球面）變為非單連通的表面（類似於環面）。二，胚胎細胞會分化為外胚層細胞、中胚層細胞、內胚層細胞（部分低等生物無中胚層細胞）。三，內胚層細胞會出現消化功能[6]。另外，儘管動物原腸胚形成的具體模式千差萬別，但總的來說原腸胚形成過程中，細胞的移動可以歸納為五種：內陷（Invagination）、內卷（Involution）、內移（Ingression）、分層（delamination）、外包（epiboly）[7]。
「原腸胚」（gastrula）以及「原腸胚形成」（gastrulation）這兩個名詞都是由恩斯特·海克爾（Ernst Haeckel）在他發表於1872年的著作《鈣質海綿生物學》（Biology of Calcareous Sponges）中首次提出的。劉易斯·沃伯特（Lewis Wolpert），發育生物學的先驅之一，曾這樣說：「出生、結婚、死亡都不是你一生中最重要的時刻，原腸胚形成才是。」[8]。
體內（羊膜上）
總覽
在羊膜（爬行類、鳥類、哺乳動物）上，原腸胚形成與原腸腔（archenteron）上出現的一個開口，胚孔的出現有密切關係。注意胚孔並不是囊胚階段上囊胚腔上的開口，而是一個新的開口。胚孔能推動囊胚表面的細胞聚合在一起。在羊膜上，原腸胚形成可以分為以下幾個大步驟：一，胚胎變為不對稱；二，原條形成；三，原條表皮細胞發生上皮-間充質轉換。同時，原條區域細胞發生內移，形成胚層[4]。
原口動物（protostome）和後口動物（deuterostome）口肛發生的差異在於，原口動物口的發生先於肛門，胚孔會發育為口。而後口動物口的發生後於肛門，胚孔會發育為肛門。它們的英文名也正是據此而來：原口動物（protostome）的英文名來自兩個希臘語單詞：「πρώτος + στόμα」，意思分別為「先」和「口」。後口動物（deuterostom）的英文名同樣來自兩個希臘單詞：「δεύτερος + στόμα」，意思分別是「第二」（次）和「口」。
對稱性的失去
在原腸胚形成的準備階段，胚胎會形成遠近軸（proximal-distal axis）以及前後軸（anterior-posterior axis），不對稱性也隨這兩個軸的發生而出現。胚胎的卵圓筒形成標誌着遠近軸的形成：近端的胚胎外組織會形成胎盤樣組織，而遠端則是上胚層。骨塑型蛋白（BMP）、成纖維細胞生長因子（FGF）、Nodal、Wnt等信號分子介導的信號轉導途徑參與了這一過程。內臟內胚層包圍表皮。遠端內臟內胚層（DVE）會遷移到胚胎的前部，形成前內臟內胚層（AVE），打破前後對稱性。上述過程受Nodal信號通路的調控[4]。
原條的產生
原條在原腸胚形成的初始階段產生。原條位於後側胚胎外組織以及表皮之間的連結處以及內移發生的區域[9]。原條的形成與科氏鐮區域的細胞中的NODAL信號通路以及由胚胎外組織激活的BMP4信號通路有很大關係[4][9][10]。Cer1和Lefty1通過拮抗Nodal信號通路，能將原條形成限制在特定區域[11]。原條區域（在形成後）會繼續往遠端生長[4]。
During the early stages of development, the primitive streak is the structure that will establish bilateral symmetry, determine the site of gastrulation and initiate germ layer formation. To form the streak, reptiles, birds and mammals arrange mesenchymal cells along the prospective midline, establishing the first embryonic axis, as well as the place where cells will ingress and migrate during the process of gastrulation and germ layer formation.[12] The primitive streak extends through this midline and creates the antero-posterior body axis,[13] becoming the first symmetry-breaking event in the embryo, and marks the beginning of gastrulation.[14] This process involves the ingression of mesoderm and endoderm progenitors and their migration to their ultimate position,[13][15] where they will differentiate into the three germ layers.[12] The localization of the cell adhesion and signaling molecule beta-catenin is critical to the proper formation of the organizer region that is responsible for initiating gastrulation.
上皮-間充質轉換與內移
In order for the cells to move from the epithelium of the epiblast through the primitive streak to form a new layer, the cells must undergo an epithelial to mesenchymal transition (EMT) to lose their epithelial characteristics, such as cell-cell adhesion. FGF signaling is necessary for proper EMT. FGFR1 is needed for the up regulation of SNAI1, which down regulates E-cadherin, causing a loss of cell adhesion. Following the EMT, the cells ingress through the primitive streak and spread out to form a new layer of cells or join existing layers. FGF8 is implicated in the process of this dispersal from the primitive streak.[11]
體外原腸胚形成
許多科學家都在嘗試通過體外實驗的方法與胚胎實驗進行對比對照，以更加深入的研究原腸胚形成的過程。通常，研究人員會使用2D（傳統）或[16][17][18]3D（培養擬原腸胚（Gastruloid）的細胞培養方法[19][20]培養胚胎幹細胞（ESC）或人工誘導性多能幹細胞（iPSC）。基於多種組織培養方法的體外培養方法相比體內實驗的方法有成本低、符合3R原則、能以空間和時間特異性的方式準確地使用激動劑/拮抗劑等優勢（在體內的原腸胚發生時期就很難做到第三點）。不過，體外實驗多少會和體內實驗存在差異，因而與體內的胚胎發育進行對比是必要的[20]。
To illustrate this, the guided differentiation of mouse ESCs has resulted in generating primitive streak-like cells that display many of the characteristics of epiblast cells that traverse through the primitive streak[16] (e.g. transient brachyury up regulation and the cellular changes associated with an epithelial to mesenchymal transition[16]), and human ESCs cultured on micro patterns, treated with BMP4, can generate spatial differentiation pattern similar to the arrangement of the germ layers in the human embryo.[17][18] Finally, using 3D embryoid body- and organoid-based techniques, small aggregates of mouse ESCs (Embryonic Organoids, or Gastruloids) are able to show a number of processes of early mammalian embryo development such as symmetry-breaking, polarisation of gene expression, gastrulation-like movements, axial elongation and the generation of all three embryonic axes (anteroposterior, dorsoventral and left-right axes).[19][20]
參見
參考
- ^ Mundlos 2009: p. 422 （頁面存檔備份，存於互聯網檔案館）
- ^ 2.0 2.1 McGeady, 2004: p. 34
- ^ Hall, 1998: pp. 132-134 （頁面存檔備份，存於互聯網檔案館）
- ^ 4.0 4.1 4.2 4.3 4.4 Arnold & Robinson, 2009
- ^ Hall, 1998: p. 177 （頁面存檔備份，存於互聯網檔案館）
- ^ Harrison 2011: p. 206 （頁面存檔備份，存於互聯網檔案館）
- ^ Gilbert 2010: p. 164.
- ^ Ereskovsky 2010: p. 236 （頁面存檔備份，存於互聯網檔案館）
- ^ 9.0 9.1 Tam & Behringer, 1997
- ^ Catala, 2005: p. 1535 （頁面存檔備份，存於互聯網檔案館）
- ^ 11.0 11.1 Tam, P.P.; Loebel, D.A. Gene function in mouse embryogenesis: get set for gastrulation. Nat Rev Genet. 2007, 8 (5): 368–81. PMID 17387317. doi:10.1038/nrg2084.
- ^ 12.0 12.1 Mikawa T, Poh AM, Kelly KA, Ishii Y, Reese DE. Induction and patterning of the primitive streak, an organizing center of gastrulation in the amniote.. Dev Dyn. 2004, 229 (3): 422–32. PMID 14991697. doi:10.1002/dvdy.10458.
- ^ 13.0 13.1 Downs KM. The enigmatic primitive streak: prevailing notions and challenges concerning the body axis of mammals.. BioEssays. 2009, 31 (8): 892–902. PMC 2949267
. PMID 19609969. doi:10.1002/bies.200900038.
- ^ Chuai M, Zeng W, Yang X, Boychenko V, Glazier JA, Weijer CJ. Cell movement during chick primitive streak formation.. Dev Biol. 2006,. 296(1)) (1): 137–49. PMC 2556955 . PMID 16725136. doi:10.1016/j.ydbio.2006.04.451.
- ^ Chuai M, Weijer CJ. The mechanisms underlying primitive streak formation in the chick embryo.. Curr Top Dev Biol. 2008, 81: 135–56. PMID 18023726. doi:10.1016/S0070-2153(07)81004-0.
- ^ 16.0 16.1 16.2 Turner, David A.; Rué, Pau; Mackenzie, Jonathan P.; Davies, Eleanor; Martinez Arias, Alfonso. Brachyury cooperates with Wnt/β-catenin signalling to elicit primitive-streak-like behaviour in differentiating mouse embryonic stem cells. BMC Biology. 2014-01-01, 12: 63. ISSN 1741-7007. PMC 4171571 . PMID 25115237. doi:10.1186/s12915-014-0063-7.
- ^ 17.0 17.1 Warmflash, Aryeh; Sorre, Benoit; Etoc, Fred; Siggia, Eric D; Brivanlou, Ali H. A method to recapitulate early embryonic spatial patterning in human embryonic stem cells. Nature Methods: 847–854. PMC 4341966 . PMID 24973948. doi:10.1038/nmeth.3016.
- ^ 18.0 18.1 Etoc, Fred; Metzger, Jakob; Ruzo, Albert; Kirst, Christoph; Yoney, Anna; Ozair, M. Zeeshan; Brivanlou, Ali H.; Siggia, Eric D. A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization. Developmental Cell: 302–315. [2017-01-27]. doi:10.1016/j.devcel.2016.09.016. （原始內容存檔於2020-08-15）.
- ^ 19.0 19.1 Brink, Susanne C. van den; Baillie-Johnson, Peter; Balayo, Tina; Hadjantonakis, Anna-Katerina; Nowotschin, Sonja; Turner, David A.; Arias, Alfonso Martinez. Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells. Development. 2014-11-15, 141 (22): 4231–4242 [2017-01-27]. ISSN 0950-1991. PMC 4302915 . PMID 25371360. doi:10.1242/dev.113001. （原始內容存檔於2020-06-12） （英語）.
- ^ 20.0 20.1 20.2 Turner, David Andrew; Glodowski, Cherise R.; Luz, Alonso-Crisostomo; Baillie-Johnson, Peter; Hayward, Penny C.; Collignon, Jérôme; Gustavsen, Carsten; Serup, Palle; Schröter, Christian. Interactions between Nodal and Wnt signalling Drive Robust Symmetry Breaking and Axial Organisation in Gastruloids (Embryonic Organoids). bioRxiv. 2016-05-13: 051722 [2017-01-27]. doi:10.1101/051722. （原始內容存檔於2018-06-04） （英語）.
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- Gilbert, Scott F. Developmental Biology Ninth. Sinauer Associates. 2010. ISBN 978-0-87893-558-1.
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- McGeady, Thomas A. (編). Gastrulation. Veterinary embryology. Wiley-Blackwell. 2006 [2017-01-27]. ISBN 978-1-4051-1147-8. （原始內容存檔於2020-07-02）.
- Mundlos, Stefan. Gene action: developmental genetics. Speicher, Michael et al (編). Vogel and Motulsky's Human Genetics: Problems and Approaches 4th. Springer. 2009. ISBN 978-3-540-37653-8. doi:10.1007/978-3-540-37654-5.
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- Sanes, Dan H. et al. Early embryology of metazoans. Development of the nervous system 2nd. Academic Press. 2006: 1–2 [2017-01-27]. ISBN 978-0-12-618621-5. （原始內容存檔於2019-05-14）.
- Stanger, Ben Z. & Melton, Douglas A. Development of Endodermal Derivatives in the Lungs, Liver, Pancreas, and Gut. Epstein, Charles J. et al (編). Inborn errors of development: the molecular basis of clinical disorders of morphogenesis. Oxford University Press. 2004. ISBN 978-0-19-514502-1.