Genetic regulation of developmental clocks

发育时钟的遗传调控

• 批准号: RGPIN-2021-02580
• 负责人: Chu, LiFang(Jack)
• 金额: $ 2.7万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742088
• 关键词: Genetic; regulation; developmental; clocks

Why do humans have a nine-month gestation period and mice have a three-week gestation period? It makes sense that more time is required to create a larger body mass, but how the timing of developmental events coordinates with species-specific differences in growth is largely unknown. Remarkably, the in vitro differentiation rate of pluripotent stem cells (PSCs) recapitulates species-specific developmental timing in vivo. Thus, many differentiation protocols using primate PSCs may require several months or sometimes years to complete, reflecting a longer gestation period. On the other hand, murine PSCs complete the same events in vitro in just days or weeks, reflecting a three-week gestation period. These observations suggest that even without normal developmental cues from intact embryonic and extraembryonic components, an intrinsic development timing/clock mechanism exists in cells. Therefore, a comparative analysis using an in vitro differentiation paradigm will help understand and characterize the fundamental mechanisms regulating developmental timing. The long-term goal of my research program is to determine the mechanisms regulating developmental timing, understand developmental clocks, and identify the factors that can modify the clock tempo. We recently established in vitro segmentation clock models using PSC-derived mesoderm progenitors, recapitulating species-specific gene oscillatory periodicity in vivo. Thus, our overarching hypothesis is that species-specific genetic factors play a central role in regulating developmental timing. Equipped with our novel in vitro developmental clock systems, this Discovery Grant application specifically aims to: 1) determine the tunable factors in the NOTCH signaling pathway that regulate the synchronization and periodicity of the segmentation clock; 2) determine if extrinsic or intrinsic factors could regulate species-specific clock periodicity; and 3) identify the links between the segmentation clock and HOX clock. The completion of these aims will not only shed light on the molecular mechanisms controlling a developmental clock during vertebrae development, but also provide a road map to understand how cells and tissues cooperate to make essential body plans. A basic understanding of developmental timing may ultimately lead to methods to accelerate the duration of in vitro differentiation and decouple it from in vivo gestation length. Notably, because developmental timing, body size, metabolic rate, and life span are all interconnected, understanding what controls timing during embryogenesis may offer new insights into what controls tissue regeneration and the aging processes.

为什么人类有九个月的妊娠期，而老鼠有三周的妊娠期？创造一个更大的身体质量需要更多的时间，这是有道理的，但发育事件的时间如何与物种特定的生长差异相协调在很大程度上是未知的。值得注意的是，多能干细胞(PSCs)的体外分化率概括了体内物种特定的发育时间。因此，许多使用灵长类PSCs的分化方案可能需要几个月甚至几年的时间才能完成，这反映了较长的妊娠期。另一方面，小鼠的PSCs在体外只需几天或几周就能完成同样的活动，这反映了三周的妊娠期。这些观察表明，即使没有完整的胚胎和胚外成分的正常发育线索，细胞中也存在内在的发育计时/时钟机制。因此，使用体外分化范式的比较分析将有助于理解和表征调控发育时机的基本机制。我的研究计划的长期目标是确定调节发育计时的机制，了解发育时钟，并确定可以改变时钟节奏的因素。我们最近利用PSC来源的中胚层前体细胞建立了体外分段时钟模型，重现了体内特定物种的基因振荡周期。因此，我们的主要假设是，物种特有的遗传因素在调节发育时机方面发挥着核心作用。配备了我们的新型体外发育时钟系统，Discovery Grant的具体目的是：1)确定Noch信号通路中调节分段时钟的同步性和周期性的可调因素；2)确定外部或内在因素是否可以调节物种特有的时钟周期；以及3)确定分段时钟和Hox时钟之间的联系。这些目标的完成不仅将阐明脊椎发育过程中控制发育时钟的分子机制，而且还将为理解细胞和组织如何合作制定基本的身体计划提供路线图。对发育时间的基本了解可能最终导致加速体外分化持续时间的方法，并将其与体内妊娠长度脱钩。值得注意的是，由于发育时间、身体大小、代谢率和寿命都是相互关联的，了解胚胎发生过程中控制时间的因素可能会为控制组织再生和衰老过程提供新的见解。