Circadian clock regulation of developmental time in the kidney

We report the emergence of an endogenous circadian clock in mouse fetal kidney that regulates organogenesis. We detect circadian rhythms both in vivo with transcriptional profiling and ex vivo by bioluminescence. High-resolution structural analysis of embryonic explants reveals that global or local clock disruption results in defects that resemble human congenital abnormalities of the kidney. The onset of fetal rhythms strongly correlates with the timing of a distinct transition in branching and growth rates during a gestational window of high fetal growth demands. Defects in clock mutants typically have been attributed to accelerated aging, however, our study establishes a role for the fetal circadian clock as a developmental timer that regulates the pathways that control organogenesis, branching rate and nephron number, and thus plays a fundamental role in kidney development. Examination of RNA-seq time series of developing fetal mouse kidneys from embryonic ages E18 to E20.5 (inclusive)本研究报道了小鼠胎肾中内源性生物钟（circadian clock）的出现及其对器官发生（organogenesis）的调控作用。研究通过体内转录组分析（transcriptional profiling）与体外（ex vivo）生物发光（bioluminescence）检测，均观测到昼夜节律信号。对胚胎外植体（embryonic explants）的高分辨率结构分析显示，整体或局部生物钟紊乱会引发类似人类先天性肾脏异常的发育缺陷。胎鼠昼夜节律的出现时机，与胎儿处于高生长需求的妊娠窗口内，肾脏分支速率与生长速率发生显著转变的时间高度吻合。此前，生物钟突变体的相关缺陷通常被归因于加速衰老，但本研究证实，胎儿生物钟可作为发育计时器（developmental timer），调控控制器官发生、分支速率与肾单位数量（nephron number）的信号通路，进而在肾脏发育中发挥基础性作用。本研究对胚胎发育阶段E18至E20.5（含）的小鼠胎肾发育RNA测序时间序列（RNA-seq time series）进行了分析。