Sox10 contributes to the balance of fate choice in dorsal root ganglion progenitors.
Sox10 contributes to the balance of fate choice in dorsal root ganglion progenitors.
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DOI：
10.1371/journal.pone.0172947
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Kelsh RN
中科院分区：
文献类型：
--
作者：
Delfino-Machín M;Madelaine R;Busolin G;Nikaido M;Colanesi S;Camargo-Sosa K;Law EW;Toppo S;Blader P;Tiso N;Kelsh RN
功能性外周神经节的发育需要神经元和神经胶质成分的平衡。在发育中的背根神经节（DRG）中，这些成分由源自神经嵴的部分受限的双能神经胶质前体形成。在小鼠和鸡中的工作已经确定了几个因素，包括Delta/Notch信号传导，这些组件的平衡的规范所需的。我们先前已经在斑马鱼中表明，Sry相关的HMG结构域转录因子Sox 10在体内感觉神经元命运规范中起着意想不到但至关重要的作用。在同一项研究中，我们描述了一种新的Sox 10突变等位基因sox 10 baz 1，其中感觉神经元数量高于野生型。在这里，我们调查这种神经原性表型的起源。我们表明，多余的神经元是感觉神经元，肠和交感神经元几乎不存在，就像在经典的sox 10无效等位基因;外周神经胶质细胞的发展也严重废除了类似于其他sox 10突变等位基因的方式。在发展中的DRG中的增殖和凋亡的检查揭示了在野生型和sox 10 baz 1中这两个过程的非常低的水平，排除了作为感觉神经元过度生产的解释的这些平衡的变化。使用化学抑制的Delta-Notch-Notch信号，我们证明，在胚胎斑马鱼，在小鼠和鸡，侧抑制在躯干DRG发展的阶段需要实现胶质细胞和神经元数量之间的平衡。然而，重要的是，我们表明，这种机制是不足以解释定量方面的baz 1表型。Sox 10（baz 1）蛋白在DNA结合HMG结构域中显示出单个氨基酸取代;结构分析表明，这种变化可能导致HMG结构域的灵活性降低，与Sox 10结合DNA的序列特异性修饰一致。与其他Sox 10突变蛋白不同，Sox 10（baz 1）保留了驱动神经生成素1转录的能力。我们表明，neurogenin 1的过表达足以在野生型背景下产生多余的背根神经节感觉神经元，并且可以以与baz 1表型非常相似的方式拯救sox 10 morphants的感觉神经元表型。我们的结论是，神经元和神经胶质细胞的命运规格的不平衡的结果从Sox 10（巴兹1）蛋白的独特能力，驱动感觉神经元规格，而未能驱动神经胶质细胞的发展。sox 10 baz 1表型首次揭示了Notch依赖的侧抑制机制不足以完全解释发育中DRG中神经元和神经胶质细胞的平衡，第二个Sox 10依赖机制是必要的。因此，Sox 10是实现感觉神经元和神经胶质命运平衡的关键转录因子。
The development of functional peripheral ganglia requires a balance of specification of both neuronal and glial components. In the developing dorsal root ganglia (DRGs), these components form from partially-restricted bipotent neuroglial precursors derived from the neural crest. Work in mouse and chick has identified several factors, including Delta/Notch signaling, required for specification of a balance of these components. We have previously shown in zebrafish that the Sry-related HMG domain transcription factor, Sox10, plays an unexpected, but crucial, role in sensory neuron fate specification in vivo. In the same study we described a novel Sox10 mutant allele, sox10baz1, in which sensory neuron numbers are elevated above those of wild-types. Here we investigate the origin of this neurogenic phenotype. We demonstrate that the supernumerary neurons are sensory neurons, and that enteric and sympathetic neurons are almost absent just as in classical sox10 null alleles; peripheral glial development is also severely abrogated in a manner similar to other sox10 mutant alleles. Examination of proliferation and apoptosis in the developing DRG reveals very low levels of both processes in wild-type and sox10baz1, excluding changes in the balance of these as an explanation for the overproduction of sensory neurons. Using chemical inhibition of Delta-Notch-Notch signaling we demonstrate that in embryonic zebrafish, as in mouse and chick, lateral inhibition during the phase of trunk DRG development is required to achieve a balance between glial and neuronal numbers. Importantly, however, we show that this mechanism is insufficient to explain quantitative aspects of the baz1 phenotype. The Sox10(baz1) protein shows a single amino acid substitution in the DNA binding HMG domain; structural analysis indicates that this change is likely to result in reduced flexibility in the HMG domain, consistent with sequence-specific modification of Sox10 binding to DNA. Unlike other Sox10 mutant proteins, Sox10(baz1) retains an ability to drive neurogenin1 transcription. We show that overexpression of neurogenin1 is sufficient to produce supernumerary DRG sensory neurons in a wild-type background, and can rescue the sensory neuron phenotype of sox10 morphants in a manner closely resembling the baz1 phenotype. We conclude that an imbalance of neuronal and glial fate specification results from the Sox10(baz1) protein’s unique ability to drive sensory neuron specification whilst failing to drive glial development. The sox10baz1 phenotype reveals for the first time that a Notch-dependent lateral inhibition mechanism is not sufficient to fully explain the balance of neurons and glia in the developing DRGs, and that a second Sox10-dependent mechanism is necessary. Sox10 is thus a key transcription factor in achieving the balance of sensory neuronal and glial fates.