Bmps and id2a act upstream of Twist1 to restrict ectomesenchyme potential of the cranial neural crest.
Bmps and id2a act upstream of Twist1 to restrict ectomesenchyme potential of the cranial neural crest.
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DOI：
10.1371/journal.pgen.1002710
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Crump JG
中科院分区：
文献类型：
--
作者：
Das A;Crump JG
颅神经嵴细胞（CNCC）具有产生外周神经系统的非外胚间充质衍生物和脊椎动物头部骨骼的外胚间充质前体的显著能力，然而这些不同的谱系是如何被指定的还不很清楚。尽管在小鼠中的研究已经表明Twist 1转录因子对于外胚间充质发育是重要的，但其在CNCC谱系决定中的作用和调节仍然不清楚。在这里，我们表明，Twist 1基因在促进外胚间充质中起着至关重要的作用，在斑马鱼的非外胚间充质基因的表达为代价。Twist 1通过促进Fgf信号传导以及通过保守的外胚间充质特异性增强子潜在地直接激活fli 1a表达来实现这一点。我们还表明，Id 2a限制Twist 1活动的外胚间充质细胞系，BMP活性优先诱导id 2a在非外胚间充质细胞前体的表达。因此，我们建议，腹侧迁移CNCC远离BMPs的来源，在背外胚层促进外胚间充质发育，通过缓解Id 2a依赖性抑制Twist 1功能。总之，我们的模型显示了如何整合BMP抑制在其起源和FGF激活沿着其迁移路线将赋予时间和空间的特异性，从神经嵴的外胚间充质的产生。脊椎动物发育中一个令人着迷的问题是，一个单一的细胞群--颅神经嵴--是如何创造出像周围神经系统和头部骨骼这样不同类型的结构的。迄今为止，指导神经嵴细胞以神经系统为代价发育成头部骨骼的分子信号仍然难以捉摸。这些信号难以识别的一个原因是它们可能在发育的多个阶段都需要，比如神经嵴细胞本身的出现。为了克服这一挑战，我们在斑马鱼中开发了一种转基因系统，使我们能够在神经嵴细胞命运确定的阶段精确地改变信号。在这样做的过程中，我们发现神经嵴细胞的早期运动使它们能够逃脱出生地抑制信号的影响，这反过来又启动了一个级联反应，关闭了神经系统基因，打开了头部骨骼基因。总之，我们的研究表明，神经嵴细胞运动的时机如何在偏置早期神经嵴细胞形成头部骨骼中发挥重要作用。
Cranial neural crest cells (CNCCs) have the remarkable capacity to generate both the non-ectomesenchyme derivatives of the peripheral nervous system and the ectomesenchyme precursors of the vertebrate head skeleton, yet how these divergent lineages are specified is not well understood. Whereas studies in mouse have indicated that the Twist1 transcription factor is important for ectomesenchyme development, its role and regulation during CNCC lineage decisions have remained unclear. Here we show that two Twist1 genes play an essential role in promoting ectomesenchyme at the expense of non-ectomesenchyme gene expression in zebrafish. Twist1 does so by promoting Fgf signaling, as well as potentially directly activating fli1a expression through a conserved ectomesenchyme-specific enhancer. We also show that Id2a restricts Twist1 activity to the ectomesenchyme lineage, with Bmp activity preferentially inducing id2a expression in non-ectomesenchyme precursors. We therefore propose that the ventral migration of CNCCs away from a source of Bmps in the dorsal ectoderm promotes ectomesenchyme development by relieving Id2a-dependent repression of Twist1 function. Together our model shows how the integration of Bmp inhibition at its origin and Fgf activation along its migratory route would confer temporal and spatial specificity to the generation of ectomesenchyme from the neural crest. A fascinating question of vertebrate development is how a single cell population—the cranial neural crest—creates such different types of structures as the peripheral nervous system and head skeleton. To date, the molecular signals that instruct neural crest cells to develop into head skeleton at the expense of nervous system have remained elusive. One reason why such signals have been difficult to identify is that they may be required at multiple stages of development—such as in the emergence of neural crest cells themselves. In order to overcome this challenge, we developed a transgenic system in zebrafish that allows us to alter signaling precisely at the stage when neural crest cell fates are determined. In so doing, we have found that the early movement of neural crest cells allows them to escape the influence of suppressive signals at their birthplace, which, in turn, sets in motion a cascade that turns off nervous system genes and turns on head skeleton genes. Together, our studies show how the timing of neural crest cell movement plays a major role in biasing early neural crest cells to form the head skeleton.
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