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浙江大学学报（农业与生命科学版）
浙江大学学报（农业与生命科学版）  2022, Vol. 48 Issue (5): 543-556    DOI: 10.3785/j.issn.1008-9209.2021.09.231
综述     
脊椎动物神经管背-腹图式形成中形态素的调控作用综述
刘聪(),徐鹏飞()
浙江大学医学院，杭州 310058
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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摘要：

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    
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
收稿日期: 2021-09-23 出版日期: 2022-11-02
CLC:  Q 593.4  
基金资助: 国家重点研发计划项目(2018YFC1003203)
通讯作者: 徐鹏飞     E-mail: liucongcc@zju.edu.cn;pengfei_xu@zju.edu.cn
作者简介: 刘聪（https://orcid.org/0000-0002-9816-6564），E-mail：liucongcc@zju.edu.cn
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引用本文:

刘聪,徐鹏飞. 脊椎动物神经管背-腹图式形成中形态素的调控作用综述[J]. 浙江大学学报（农业与生命科学版）, 2022, 48(5): 543-556.

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.

链接本文:

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

图1  脊椎动物神经管背-腹图式BMP：骨形成蛋白；Shh：音猬因子；RP：顶板；FP：底板；dP1～dP6：背侧祖细胞域；dI1～dI6：背侧中间神经元群；p0～p3和pMN：腹侧祖细胞域；v0～v3和MN：腹侧中间神经元群。
图2  神经管的形成过程
图3  斑马鱼早期发育中BMP浓度梯度转换过程A.原肠胚初期，在背侧组织者分泌的BMP拮抗剂的作用下，胚胎中BMP信号形成从腹侧到背侧（从高到低）的浓度梯度。B.神经发生初期，由于胚胎的汇聚延伸运动，神经外胚层细胞迁移到背中线形成神经板，同时，神经板中线处开始内陷。此时，BMP信号在外侧浓度较高，在中线处浓度最低。C.当神经发生完成并形成神经管时，起源于原肠胚最腹侧的细胞迁移到神经管的最背侧，最终形成从背侧到腹侧（从高到低）的BMP浓度梯度。LV：侧视图；DV：背视图；AV：动物极视图；NP：神经板；NT：神经管（下同）。
图4  神经管顶板的形成过程A.神经板时期；B.早期神经嵴细胞时期；C.顶板形成时期。
图5  BMP信号转导P： 磷酸基团。
图6  Shh信号的产生、分泌和转导
图7  利用Shh浓度梯度体外指导前脑类器官的形成示意图A.利用转录激活因子样效应物核酸酶（TALEN）同源重组技术构建多西环素诱导表达SHH的H9细胞系（iSHH）；B.将iSHH细胞聚集于类器官一端作为信号源以提供Shh浓度梯度；C.在Shh浓度梯度下诱导形成有多种细胞类型的前脑类器官，并再现了体内前脑的细胞图式，包括新皮质、外侧神经节隆起、内侧神经节隆起、下丘脑前叶和下丘脑腹后叶。
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