Tempus fugit: How time flies during development

doi:10.1126/science.abe0953

GSTDTAP > 气候变化

DOI	10.1126/science.abe0953
	Tempus fugit: How time flies during development
	Ryohei Iwata; Pierre Vanderhaeghen
	2020-09-18
发表期刊	Science
出版年	2020
英文摘要	“Fugit irreparabile tempus,” wrote Virgil, a reminder that our lives are defined by the irreversible flow of time. As soon as the egg is fertilized, embryonic cells follow a developmental program strictly organized in time. The sequence typically is conserved throughout evolution, but individual events can occur over species-specific time scales. Such differences can have marked effects. For instance, it takes 3 months to generate cerebral cortex neurons in a human but only 1 week in a mouse. This prolonged neurogenesis likely contributes to evolutionary expansion of the human brain ([ 1 ][1]). But the mechanisms underlying developmental time scales remain largely unknown. On pages 1449 and 1450 of this issue, Rayon et al. ([ 2 ][2]) and Matsuda et al. ([ 3 ][3]), respectively, report an association between species-specific developmental time scales and the speed of biochemical reactions that support protein turnover. Cell differentiation during mammalian development uses two types of timing mechanisms (biological clocks) based on oscillations or unidirectional processes (hourglass clocks). Modeling development in pluripotent stem cells (PSCs) from various species shows that the pace of differentiation of many cell types in an in vitro setting largely recapitulates the species-specific timing observed in embryos ([ 4 ][4], [ 5 ][5]). Even when human neurons are transplanted as single cells in a mouse brain, they follow their own prolonged developmental timeline ([ 6 ][6]). This suggests that cell-intrinsic mechanisms, yet to be discovered, dictate the timing of developmental trajectories in a species-specific manner. Matsuda et al. examined a biological rhythm typical of vertebrate embryos: the “somite segmentation clock,” by which the body is built segment (or somite) by segment, thanks to waves of expression of specific genes (oscillations) in presomitic mesodermal (PSM) cells. Using in vitro modeling with mouse and human PSCs, the authors examined waves of expression of HES7 (hes family bHLH transcription factor 7), a segmental-clock master gene. They found similar waves in PSM cells of both species, but the period of oscillations in human cells was ∼5 hours instead of 2 hours (as in mouse cells), consistent with another recent report ([ 7 ][7]). What might underlie such cell-intrinsic differences? Evolutionary divergence in developmental processes usually occurs as a result of changes in the gene regulatory networks (GRNs) that control them ([ 8 ][8]). The authors examined the GRN of segmental oscillations, and except for the period of oscillation, they found no obvious difference between human and mouse gene expression. They then swapped the mouse and human genome sequences containing the HES7 locus. The human HES7 gene transplanted in mouse cells displayed fast oscillations like the mouse gene, whereas the mouse gene transplanted in the human cells displayed slower, human-like oscillations (see the figure). Thus, even DNA cis-regulatory components of the GRN do not appear to dictate the time scale of HES7 oscillations. However, Matsuda et al. found important species-specific differences in a different mechanism: the speed of biochemical reactions leading to protein turnover (production and decay). Human cells displayed slower kinetics of protein expression (including “expression delays” related to RNA transcription, splicing, and translation) and a slower rate of protein decay, mostly related to degradation. Many examined parameters showed a twofold difference in mouse versus human cells, matching the time differences observed for the segmentation clock. ![Figure][9] Same events, distinct timingGRAPHIC: KELLIE HOLOSKI/ SCIENCE Rather than being dominated by clocklike oscillations, the developmental process is specified mostly by cell-fate transitions, by which embryonic cells gradually an d irreversibly become differentiated cells. Could it be that similar mechanisms regulate these hourglass-like timing events as well? Rayon et al. explored this notion using a motor neuron (MN) developmental model from mouse and human PSCs. Examination of MN development in vitro revealed that the underlying GRN is similar in both species, except that human motoneurogenesis takes 2.5 times longer in the human cell model versus the mouse. The authors then examined the influence of sonic hedgehog, the key morphogen that induces MN fate (by changing timing and intensity of the signal), and the MN-development master gene OLIG2 (oligodendrocyte transcription factor 2) (by inserting the human gene in mouse cells) but found no effects that explained the species-specific time differences. They then analyzed protein stability during MN development and found that the mean protein half-life was doubled in human cells compared with mouse cells, which is consistent with the findings of Matsuda et al. Both studies point to protein turnover as a potential source of variation in developmental time scales. Each group tested this hypothesis further by in silico modeling of their experimental systems, which predicted, in each case, a prominent influence of the delay in protein production and protein decay on developmental time scales. That protein turnover affects the timing of development is provocative and attractive but must be validated by experimental evidence for causal relationship between the two (by altering the production and decay of proteins and mRNA, and then examining the developmental time scale). Such experiments will also help to determine the respective contributions of expression delay versus protein decay, on which each study puts a somewhat different emphasis. The consistent results from both studies also raise questions about the mechanisms upstream of interspecies differences in protein turnover. Metabolism is an attractive candidate. Protein turnover requires a considerable amount of energy ([ 9 ][10]), and metabolic rewiring has emerged as a central instructor of cell fate transitions ([ 10 ][11]), although through epigenetic remodeling rather than changes in proteostasis. Another question is whether the same principles apply to developmental events that display more pronounced time scale differences. For example, GRN divergence might operate through specific genes that modulate the timing of human cortical neurogenesis ([ 11 ][12]). Furthermore, metabolism and protein turnover might display differences depending on the cell context or the specific protein involved. And known correlations between developmental timing, life span, and aging across species ([ 12 ][13]) might all be causally linked to differences in metabolism and protein turnover. 1. [↵][14]1. A. M. M. Sousa et al ., Cell 170, 226 (2017). [OpenUrl][15][CrossRef][16][PubMed][17] 2. [↵][18]1. T. Rayon et al ., Science 369, eaba7667 (2020). [OpenUrl][19][Abstract/FREE Full Text][20] 3. [↵][21]1. M. Matsuda et al ., Science 369, 1450 (2020). [OpenUrl][22][Abstract/FREE Full Text][23] 4. [↵][24]1. J. van den Ameelen et al ., Trends Neurosci. 37, 334 (2014). 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[OpenUrl][52][CrossRef][53][PubMed][54] Acknowledgments: P.V. is funded by the European Research Council, Belgian Fonds Wetenschappelijk Onderzoek, Excellence of Science Research programme, AXA Research Fund, Belgian Queen Elizabeth Foundation, and Fondation Université Libre de Bruxelles. R.I. was supported by the Belgian Fonds de la Recherche Scientifique. 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领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/295414
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Ryohei Iwata,Pierre Vanderhaeghen. Tempus fugit: How time flies during development[J]. Science,2020.
APA	Ryohei Iwata,&Pierre Vanderhaeghen.(2020).Tempus fugit: How time flies during development.Science.
MLA	Ryohei Iwata,et al."Tempus fugit: How time flies during development".Science (2020).