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浙江大学学报（农业与生命科学版）
Journal of Zhejiang University (Agriculture and Life Sciences)  2022, Vol. 48 Issue (5): 543-556    DOI: 10.3785/j.issn.1008-9209.2021.09.231
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Review on regulatory role of morphogens in the formation of dorsal-ventral pattern of vertebrate neural tube
Cong LIU(),Pengfei XU()
College of Medicine, Zhejiang University, Hangzhou 310058, China
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Abstract  

In vertebrates, the development of the central nervous system depends on the correct patterning of the neural tube along its anterior-posterior and dorsal-ventral axes in the early embryo as well as the underlying regulation of the cell differentiation. During the neural tube formation, the arrangement of the precursor cells depends on the regulation of different morphogen concentration gradients. The most important morphogens during the neural tube development are the bone morphogenetic protein (BMP) secreted from the roof plate and the Sonic hedgehog (Shh) secreted from the floor plate, which would form an antiparallel concentration gradient in the neural tube. These morphogen concentration gradients could further provide the positional information to the precursor cells and gradually determine their differentiation fate. In this paper, we summarized the process of neural tube development in different model organisms, focusing on the important role of two morphogens of BMP and Shh in the formation of dorsal-ventral pattern of the neural tube. Besides, a better understanding of the developmental mechanism of the nervous system in vivo would also provide some insights on the construction of neural tube organoids in vitro. Therefore, we also pointed out the latest progress of neural tube organoids and discussed the future perspective of this field.

Key words： morphogen      neural tube development      bone morphogenetic protein      Sonic hedgehog      organoid     
Received: 23 September 2021      Published: 02 November 2022
CLC:  Q 593.4  
Corresponding Authors: Pengfei XU     E-mail: liucongcc@zju.edu.cn;pengfei_xu@zju.edu.cn
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Cite this article:

Cong LIU,Pengfei XU. Review on regulatory role of morphogens in the formation of dorsal-ventral pattern of vertebrate neural tube. Journal of Zhejiang University (Agriculture and Life Sciences), 2022, 48(5): 543-556.

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https://www.zjujournals.com/agr/10.3785/j.issn.1008-9209.2021.09.231     OR     https://www.zjujournals.com/agr/Y2022/V48/I5/543


脊椎动物神经管背-腹图式形成中形态素的调控作用综述

脊椎动物中枢神经系统的形成依赖于胚胎早期神经管前-后、背-腹等图式的正确建立和后期细胞分化的精细调控。在神经管形成过程中，其前体细胞受到形态素浓度梯度的调控，沿着身体背-腹轴方向呈有规律的排列，其中最重要的2种形态素是骨形成蛋白（bone morphogenetic protein, BMP）和音猬因子（Sonic hedgehog, Shh）。从顶板分泌的BMP和从底板分泌的Shh在神经管中形成反向平行的浓度梯度，神经前体细胞在这些形态素的作用下获得其位置信息并逐渐决定其分化命运。本文系统总结了不同模式生物神经管发育的相关研究，着重综述了BMP和Shh这2种形态素在脊椎动物神经管背-腹图式形成中的重要作用。此外，对神经系统在体内发育机制的更深理解可为体外构建神经管类器官提供指导，因此，在本综述的最后，我们总结了神经管类器官培养的最新进展，并探讨了其未来发展策略。


关键词： 形态素,  神经管发育,  骨形成蛋白,  音猬因子,  类器官 
Fig. 1 Dorsal-ventral pattern of vertebrate neural tubeBMP: Bone morphogenetic protein; Shh: Sonic hedgehog; RP: Roof plate; FP: Floor plate; dP1-dP6: Dorsal progenitor domains; dI1-dI6: Dorsal interneuron populations; p0-p3 and pMN: Ventral progenitor domains; v0-v3 and MN: Ventral interneuron populations.
Fig. 2 Formation process of neural tube
Fig. 3 BMP concentration gradient shifting process during the zebrafish early developmentA. At the beginning of the gastrulation, the BMP antagonists secreted from the dorsal organizer result in a ventral to dorsal (high to low) BMP concentration gradient. B. At the beginning of the neurulation, because of the convergence and extension, the neuroectodermal cells migrate to the dorsal midline; at the same time, the neural plate forms. At this moment, the BMP concentration gradient is higher at the lateral, and the cells at the midline start to invaginate where the BMP concentration is the lowest. C. When the neurulation is completed and the neural tube is formed, the cells that originate from the most ventral side of the gastrula now migrate to the most dorsal side of the neural tube, where forms an eventual dorsal to ventral (high to low) BMP concentration gradient. LV: Lateral view; DV: Dorsal view; AV: Animal view; NP: Neural plate; NT: Neural tube (the same as below).
Fig. 4 Formation process of roof plate in neural tubeA. Neural plate stage; B. Early neural crest cell stage; C. Roof plate formation stage.
Fig. 5 BMP signaling transductionP: Phosphate group.
Fig. 6 Production, secretion and transduction of Shh signaling
Fig. 7 Schematic description of applying Shh concentration gradient to instruct forebrain organoid formation in vitroA. A doxycycline-inducible Shh H9 cell line (iSHH) was generated using transcription activator-like effector nucleases (TALEN) homologous recombination technology; B. iSHH cells were aggregated and fused to one side of the organoid to establish the Shh concentration gradient; C. By exposed to different concentrations of Shh, a forebrain organoid was induced and could recapitulate the topography of the in vivo forebrain, which included multiple cell types like neocortex, lateral ganglionic eminence, medial ganglionic eminence, anterior hypothalamus, and ventro-posterior hypothalamus.
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