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Species-specific pace of development is associated with differences in protein stability
Science ( IF 56.9 ) Pub Date : 2020-09-17 , DOI: 10.1126/science.aba7667
Teresa Rayon 1 , Despina Stamataki 1 , Ruben Perez-Carrasco 1, 2, 3 , Lorena Garcia-Perez 1 , Christopher Barrington 1 , Manuela Melchionda 1 , Katherine Exelby 1 , Jorge Lazaro 1 , Victor L J Tybulewicz 1, 4 , Elizabeth M C Fisher 5 , James Briscoe 1
Affiliation  

Setting the tempo for development Many animals display similarities in their organization (body axis, organ systems, and so on). However, they can display vastly different life spans and thus must accommodate different developmental time scales. Two studies now compare human and mouse development (see the Perspective by Iwata and Vanderhaeghen). Matsuda et al. studied the mechanism by which the human segmentation clock displays an oscillation period of 5 to 6 hours, whereas the mouse period is 2 to 3 hours. They found that biochemical reactions, including protein degradation and delays in gene expression processes, were slower in human cells compared with their mouse counterparts. Rayon et al. looked at the developmental tempo of mouse and human embryonic stem cells as they differentiate to motor neurons in vitro. Neither the sensitivity of cells to signals nor the sequence of gene-regulatory elements could explain the differing pace of differentiation. Instead, a twofold increase in protein stability and cell cycle duration in human cells compared with mouse cells was correlated with the twofold slower rate of human differentiation. These studies show that global biochemical rates play a major role in setting the pace of development. Science, this issue p. 1450, p. eaba7667; see also p. 1431 A comparison of mouse and human motor neuron differentiation suggests why developmental tempo differs between species. INTRODUCTION What determines the pace of embryonic development? Although the molecular and cellular mechanisms of many developmental processes are evolutionarily conserved, the pace at which these operate varies considerably between species. The tempo of embryonic development controls the rate of individual differentiation processes and determines the overall duration of development. Despite its importance, however, the mechanisms that control developmental tempo remain elusive. RATIONALE Comparing highly conserved and well-characterized developmental processes in different species permits a search for mechanisms that explain differences in tempo. The specification of neuronal subtype identity in the vertebrate spinal cord is a prominent example, lasting less than a day in zebrafish, 3 to 4 days in mouse, and around 2 weeks in human. The development of the spinal cord involves a well-defined gene regulatory program comprising a series of stereotypic changes in gene expression, regulated by extrinsic signaling as cells differentiate from neural progenitors to postmitotic neurons. The regulatory program and resulting neuronal cell types are highly similar in different vertebrates, despite the difference in tempo between species. We therefore set out to characterize the pace of differentiation of one specific neuronal subtype—motor neurons—in human and mouse and to identify molecular differences that explain differences in pace. To this end, we took advantage of the in vitro recapitulation of in vivo developmental programs using the directed differentiation of human and mouse embryonic stem cells. RESULTS We found that all stages of the developmental progression from neural progenitor to motor neuron were proportionally prolonged in human compared with mouse, resulting in human motor neuron differentiation taking about 2.5 times longer than mouse. Differences in tempo were not due to differences in the sensitivity of cells to signals, nor could they be attributed to differences in the sequence of the key genes or their regulatory elements. Instead, the data revealed that changes in protein stability correlated with developmental tempo, such that slower temporal progression in human corresponded to increased protein stability. An in silico model indicated that increased protein stability could account for the slower tempo of development in human compared with mouse. CONCLUSION The results suggest that differences in protein turnover play a role in interspecies differences in the pace of motor neuron differentiation. The identification of a molecular mechanism that can explain differences in the pace of embryonic development between species focuses attention on the role of protein stability in tempo control. This suggests a parsimonious explanation for the substantial variation in the tempo of development between species and indicates how the overall dynamics of developmental processes can be influenced by kinetic properties of gene regulation. What determines species-specific rates of protein turnover remains to be determined, but the availability of in vitro systems that mimic in vivo developmental tempo opens up the possibility of exploring this issue. Developmental tempo and protein stability. Different animal species develop at different tempos, and equivalent developmental stages can be matched between mouse and human at different developmental time points. Neural progenitors in the spinal cord progress through the same succession of gene expression to generate motor neurons in mouse and human, and this serves as a model to study tempo differences. The in vitro directed differentiation of mouse embryonic stem cells to motor neurons advances at greater than twice the speed of human embryonic stem cell differentiation. The equivalent progression of development at different rates is shown for the transcription factors PAX6 (green), OLIG2 (red), and NKX2.2 (blue). E, embryonic day; W, embryonic week; CS, Carnegie stage. Scale bars are 50 μm. Although many molecular mechanisms controlling developmental processes are evolutionarily conserved, the speed at which the embryo develops can vary substantially between species. For example, the same genetic program, comprising sequential changes in transcriptional states, governs the differentiation of motor neurons in mouse and human, but the tempo at which it operates differs between species. Using in vitro directed differentiation of embryonic stem cells to motor neurons, we show that the program runs more than twice as fast in mouse as in human. This is not due to differences in signaling, nor the genomic sequence of genes or their regulatory elements. Instead, there is an approximately two-fold increase in protein stability and cell cycle duration in human cells compared with mouse cells. This can account for the slower pace of human development and suggests that differences in protein turnover play a role in interspecies differences in developmental tempo.

中文翻译:

特定物种的发展速度与蛋白质稳定性的差异有关

为发育设定节奏 许多动物的组织结构(身体轴、器官系统等)都有相似之处。然而,它们可以显示出截然不同的寿命,因此必须适应不同的发展时间尺度。现在有两项研究比较了人类和小鼠的发育(参见 Iwata 和 Vanderhaeghen 的观点)。松田等人。研究了人类分割时钟显示振荡周期为5至6小时的机制,而鼠标周期为2至3小时。他们发现,与小鼠细胞相比,人类细胞中的生化反应,包括蛋白质降解和基因表达过程延迟,速度较慢。人造丝等人。观察了小鼠和人类胚胎干细胞在体外分化为运动神经元时的发育速度。细胞对信号的敏感性和基因调控元件的序列都不能解释不同的分化速度。相反,与小鼠细胞相比,人类细胞中蛋白质稳定性和细胞周期持续时间的两倍增加与人类分化速度的两倍慢相关。这些研究表明,全球生化率在确定发展速度方面发挥着重要作用。科学,本期第 3 页。1450 页。eaba7667; 另见第 1431 小鼠和人类运动神经元分化的比较表明为什么物种之间的发育速度不同。引言 是什么决定了胚胎发育的速度?尽管许多发育过程的分子和细胞机制在进化上是保守的,但这些过程的运行速度在物种之间差异很大。胚胎发育的节奏控制着个体分化过程的速率,并决定了发育的整体持续时间。然而,尽管它很重要,但控制发育节奏的机制仍然难以捉摸。基本原理 比较不同物种高度保守和特征明确的发育过程,可以寻找解释节奏差异的机制。脊椎动物脊髓中神经元亚型身份的规范是一个突出的例子,在斑马鱼中持续不到一天,在小鼠中持续 3 到 4 天,在人类中持续大约 2 周。脊髓的发育涉及一个明确定义的基因调控程序,包括一系列基因表达的刻板变化,当细胞从神经祖细胞分化为有丝分裂后神经元时,受外在信号的调控。尽管物种之间的节奏不同,但不同脊椎动物的调控程序和由此产生的神经元细胞类型高度相似。因此,我们开始描述人类和小鼠中一种特定神经元亚型(运动神经元)的分化速度,并确定解释速度差异的分子差异。为此,我们利用人类和小鼠胚胎干细胞的定向分化对体内发育程序进行了体外概括。结果我们发现,与小鼠相比,人类从神经祖细胞到运动神经元的所有发育阶段都按比例延长,导致人类运动神经元分化的时间比小鼠长约 2.5 倍。节奏的差异不是由于细胞对信号的敏感性不同,也不能归因于关键基因或其调控元件的序列差异。相反,数据显示蛋白质稳定性的变化与发育速度相关,因此人类较慢的时间进展对应于蛋白质稳定性的增加。计算机模型表明,与小鼠相比,增加的蛋白质稳定性可能是人类发育速度较慢的原因。结论结果表明,蛋白质周转的差异在运动神经元分化速度的种间差异中起作用。一种可以解释物种间胚胎发育速度差异的分子机制的鉴定将注意力集中在蛋白质稳定性在速度控制中的作用上。这表明对物种之间发育速度的巨大差异的简单解释,并表明发育过程的整体动态如何受到基因调控的动力学特性的影响。什么决定了特定物种的蛋白质周转率仍有待确定,但模拟体内发育速度的体外系统的可用性为探索这个问题开辟了可能性。发育速度和蛋白质稳定性。不同的动物物种以不同的速度发展,并且在不同的发育时间点,小鼠和人类之间可以匹配相同的发育阶段。脊髓中的神经祖细胞通过相同的基因表达序列在小鼠和人类中产生运动神经元,这可以作为研究节奏差异的模型。小鼠胚胎干细胞在体外定向分化为运动神经元的速度是人类胚胎干细胞分化速度的两倍以上。显示了转录因子 PAX6(绿色)、OLIG2(红色)和 NKX2.2(蓝色)在不同速率下的等效发育进程。E、胚胎日;W,胚胎周;CS,卡内基舞台。比例尺为 50 μm。尽管控制发育过程的许多分子机制在进化上是保守的,胚胎发育的速度在物种之间可能有很大差异。例如,相同的遗传程序,包括转录状态的连续变化,控制着小鼠和人类运动神经元的分化,但它的运行速度在物种之间有所不同。使用胚胎干细胞体外定向分化为运动神经元,我们表明该程序在小鼠中的运行速度是人类的两倍多。这不是由于信号传导的差异,也不是由于基因的基因组序列或其调控元件。相反,与小鼠细胞相比,人类细胞的蛋白质稳定性和细胞周期持续时间大约增加了两倍。
更新日期:2020-09-17
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