Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics.
Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics.
复制标题
DOI：
10.1371/journal.pbio.2003127
复制
发表时间：
2018-03
期刊：
影响因子：
9.8
通讯作者：
Novitch BG
中科院分区：
文献类型：
--
作者：
Sagner A;Gaber ZB;Delile J;Kong JH;Rousso DL;Pearson CA;Weicksel SE;Melchionda M;Mousavy Gharavy SN;Briscoe J;Novitch BG
在组织发育过程中，多能祖细胞以特征性的空间和时间模式分化成特定的细胞类型。我们提出了神经管中祖细胞身份和分化率的联系机制，其中运动神经元（MN）祖细胞比其他祖细胞分化更快。使用单细胞转录组学，我们定义了与神经祖细胞向MN过渡相关的转录变化。从这些数据重建基因表达动态表明MN决定因素Olig2在MN分化之前的关键作用。Olig2抑制Notch信号通路效应子Hes1和Hes5的表达。Hes5的Olig2抑制似乎是直接的，通过Hes5基因座内的保守调控元件，限制MN祖细胞的表达。这些发现揭示了控制模式和神经元分化的调控网络之间的紧密耦合，并展示了Olig2如何作为协调MN生成的空间和时间模式的发育起搏器。在发育中的组织中，正确类型的细胞是如何在正确的地方、正确的时间和正确的数量产生的？在回答这个问题方面取得进展的一个例子是胚胎脊髓。在这种组织中，细胞外信号，如形态发生素音刺猬（Shh），控制分子上不同的神经祖细胞组的生成模式，从这些神经祖细胞中生成不同类别的运动神经元和中间神经元。运动神经元的分化速度比相邻的中间神经元快得多，这确保了以适当的时间顺序产生比中间神经元更多的运动神经元。为了理解这种现象的机制，我们研究了Shh控制的基因调控网络的动力学，这些网络作为运动神经元从祖细胞形成。我们使用这些数据来揭示伴随的调控机制，这确定了转录因子Olig2的两个功能。首先，Olig2对于在Shh信号传导下游建立运动神经元祖细胞身份是必需的。随后，Olig2通过抑制神经元分化的负调节因子Hes基因的表达直接促进运动神经元祖细胞中的神经元分化。总之，我们的研究结果揭示了运动神经元祖细胞中控制模式化和神经元分化的遗传网络之间的紧密耦合，从而解释了其特征性的早期和快速的神经元分化率。
During tissue development, multipotent progenitors differentiate into specific cell types in characteristic spatial and temporal patterns. We addressed the mechanism linking progenitor identity and differentiation rate in the neural tube, where motor neuron (MN) progenitors differentiate more rapidly than other progenitors. Using single cell transcriptomics, we defined the transcriptional changes associated with the transition of neural progenitors into MNs. Reconstruction of gene expression dynamics from these data indicate a pivotal role for the MN determinant Olig2 just prior to MN differentiation. Olig2 represses expression of the Notch signaling pathway effectors Hes1 and Hes5. Olig2 repression of Hes5 appears to be direct, via a conserved regulatory element within the Hes5 locus that restricts expression from MN progenitors. These findings reveal a tight coupling between the regulatory networks that control patterning and neuronal differentiation and demonstrate how Olig2 acts as the developmental pacemaker coordinating the spatial and temporal pattern of MN generation. How are the right types of cells produced in the right place, at the right time and in the correct numbers, in a developing tissue? One example of where progress has been made towards answering this question is the embryonic spinal cord. In this tissue, extracellular signals, such as the morphogen sonic hedgehog (Shh), control the pattern of generation of molecularly distinct sets of neural progenitors, from which different classes of motor neurons and interneurons are generated. Motor neurons differentiate at a much higher rate than the adjacent interneurons, and this ensures that more motor neurons than interneurons are generated and in an appropriate temporal sequence. To understand the mechanisms responsible for this phenomenon, we investigated the dynamics of the Shh-controlled gene regulatory network operating as motor neurons form from progenitors. We used these data to uncover the accompanying regulatory mechanisms, and this identified two functions for the transcription factor Olig2. First, Olig2 is essential for establishing motor neuron progenitor identity downstream of Shh signaling. Subsequently, Olig2 directly promotes neuronal differentiation in motor neuron progenitors by suppressing the expression of Hes genes, negative regulators of neuronal differentiation. Together, our findings reveal a tight coupling between the genetic networks that control patterning and neuronal differentiation in motor neuron progenitors and thereby explain their characteristic early and rapid rate of neuronal differentiation.
登录
查看更多内容
影响因子：
9.8
作者：
Dessaud E;Ribes V;Balaskas N;Yang LL;Pierani A;Kicheva A;Novitch BG;Briscoe J;Sasai N
通讯作者：
Sasai N
影响因子：
9.8
作者：
Gaber ZB;Butler SJ;Novitch BG
通讯作者：
Novitch BG
影响因子：
4.6
作者：
Kageyama, Ryoichiro;Ohtsuka, Toshiyuki;Kobayashi, Taeko
通讯作者：
Kobayashi, Taeko
影响因子：
64.8
作者：
Dasen, JS;Liu, JP;Jessell, TM
通讯作者：
Jessell, TM
影响因子：
4
作者：
Cohen, Michael;Briscoe, James;Blassberg, Robert
通讯作者：
Blassberg, Robert