Bimodal function of chromatin remodeler Hmga1 in neural crest induction and Wnt-dependent emigration.
Bimodal function of chromatin remodeler Hmga1 in neural crest induction and Wnt-dependent emigration.
复制标题
染色质重塑剂HMGA1在神经rest诱导和Wnt依赖性移民中的双峰功能。
DOI：
10.7554/elife.57779
复制
发表时间：
2020-09-23
期刊：
影响因子：
7.7
通讯作者：
Bronner ME
中科院分区：
文献类型：
--
作者：
Gandhi S;Hutchins EJ;Maruszko K;Park JH;Thomson M;Bronner ME
在原肠胚形成过程中，神经嵴细胞在神经板边缘被指定，其特征在于Pax 7表达。使用单细胞RNA测序加上高分辨率原位杂交，以确定新的转录调节因子，我们表明，染色质重塑Hmga 1是高度表达之前，规范和保持在迁移鸡神经嵴细胞。时间控制的CRISPR-Cas9介导的敲除揭示了Hmga 1在神经嵴发育中的两种不同功能。在神经板边缘，Hmga 1调节Pax 7依赖的神经嵴谱系特化。在premigration阶段，第二个作用表现在Hmga 1损失减少颅嵴移民从背神经管独立的Pax 7。有趣的是，这被稳定的β-连环蛋白所拯救，因此暗示Hmga 1是典型的Wnt激活剂。总之，我们的研究结果表明，Hmga 1功能在神经嵴发育过程中的双峰方式，以调节规范的神经板边界，随后从神经管移民通过典型的Wnt信号。神经板是一种结构，在具有脊椎的动物的发育过程中作为大脑和中枢神经系统的基础。特别是，神经板边缘的组织成为神经嵴，这是一组高度移动的细胞，可以专门形成神经和面部的部分。允许冠出现的确切分子机制仍然未知。蛋白质Hmga 1改变了基因在细胞内的包装和组织方式，这反过来又影响了基因的开启和关闭。在这里，Gandhi等人研究了Hmga 1如何帮助塑造发育中的鸡胚胎的神经嵴。为此，他们利用了一种名为CRISPR-Cas9的遗传工具，并在特定的发育阶段删除了编码Hmga 1的基因。此操作突出显示了Hmga 1活跃的两个时期。首先，Hmga 1通过激活一种名为pax 7的基因，帮助确定神经板边缘的神经嵴细胞。然后，在稍后的阶段，Hmga 1通过触发Wnt通讯系统允许这些细胞移动到身体的其他部位。神经嵴不能正常发育会导致出生缺陷和癌症，如黑色素瘤和儿童神经母细胞瘤，这突出了更好地了解这种结构是如何形成的必要性。此外，更好地掌握Hmga 1在健康发育中的作用有助于了解它如何参与一系列成人癌症。
During gastrulation, neural crest cells are specified at the neural plate border, as characterized by Pax7 expression. Using single-cell RNA sequencing coupled with high-resolution in situ hybridization to identify novel transcriptional regulators, we show that chromatin remodeler Hmga1 is highly expressed prior to specification and maintained in migrating chick neural crest cells. Temporally controlled CRISPR-Cas9-mediated knockouts uncovered two distinct functions of Hmga1 in neural crest development. At the neural plate border, Hmga1 regulates Pax7-dependent neural crest lineage specification. At premigratory stages, a second role manifests where Hmga1 loss reduces cranial crest emigration from the dorsal neural tube independent of Pax7. Interestingly, this is rescued by stabilized ß-catenin, thus implicating Hmga1 as a canonical Wnt activator. Together, our results show that Hmga1 functions in a bimodal manner during neural crest development to regulate specification at the neural plate border, and subsequent emigration from the neural tube via canonical Wnt signaling. The neural plate is a structure that serves as the basis for the brain and central nervous system during the development of animals with a backbone. In particular, the tissues at the border of the neural plate become the neural crest, a group of highly mobile cells that can specialize to form nerves and parts of the face. The exact molecular mechanisms that allow the crest to emerge are still unknown. The protein Hmga1 alters how genes are packaged and organized inside cells, which in turn influences how genes are switched on and off. Here, Gandhi et al. studied how Hmga1 helps to shape the neural crest in developing chicken embryos. To do so, they harnessed a genetic tool called CRISPR-Cas9, and deleted the gene that encodes Hmga1 at specific developmental stages. This manipulation highlighted two periods where Hmga1 is active. First, Hmga1 helped to define neural crest cells at the neural plate border by activating a gene called pax7. Then, at a later stage, Hmga1 allowed these cells to move to other parts of the body by triggering the Wnt communication system. Failure for the neural crest to develop properly causes birth defects and cancers such as melanoma and childhood neuroblastoma, highlighting the need to better understand how this structure is formed. In addition, a better grasp of the roles of Hmga1 in healthy development could help to appreciate how it participates in a range of adult cancers.