Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Hibernation Metabolism, Physiology and Development Group, Institute of Low Temperature Science, Hokkaido University, Sapporo, Japan.
Dev Dyn. 2019 Oct;248(10):931-941. doi: 10.1002/dvdy.87. Epub 2019 Jul 26.
The timing of developmental events is tightly regulated along a time axis for normal development. Although the RNA-binding protein Lin28a plays a crucial role in the regulation of developmental timing in Caenorhabditis elegans, how the timing of Lin28a expression affects the rate and/or duration of developmental events during mammalian development remains to be addressed.
In this study, we discovered that the timing and the duration of Lin28a expression affect embryonic growth. During the neurulation stage of mouse development, endogenous Lin28a levels start to drop. When Lin28a expression was maintained transiently using the inducible tetracycline-regulated gene expression (Tet-ON) system [doxycycline (Dox)-inducible Lin28a transgenic (iLin28a Tg) mice] with Dox administration at E8.5 and E9.5, it resulted in neonatal lethality, increased body weight (organomegaly), and an increased number of caudal vertebrae at birth. On the other hand, Lin28a induction only at E8.5 caused neonatal lethality and organomegaly, but did not affect the caudal vertebra number. Of note, although Dox treatment before or after neurulation still caused neonatal lethality, it neither caused organomegaly nor the increased caudal vertebra number in iLin28a Tg neonates.
Temporal regulation of Lin28a expression during neurulation affects developmental events such as cessation of axial elongation and embryonic growth in mice.
正常发育过程中，沿时间轴严格调控发育事件的时间。虽然 RNA 结合蛋白 Lin28a 在秀丽隐杆线虫发育时间调控中起着至关重要的作用，但 Lin28a 表达的时间如何影响哺乳动物发育过程中发育事件的速度和/或持续时间仍有待解决。
在这项研究中，我们发现 Lin28a 表达的时间和持续时间会影响胚胎生长。在小鼠发育的神经胚形成阶段，内源性 Lin28a 水平开始下降。当使用诱导型四环素调控基因表达（Tet-ON）系统（Dox 诱导 Lin28a 转基因（iLin28a Tg）小鼠）在 E8.5 和 E9.5 时短暂维持 Lin28a 表达，并用 Dox 处理时，会导致新生鼠死亡、体重增加（器官肿大）和出生时尾骨数量增加。另一方面，仅在 E8.5 时诱导 Lin28a 表达会导致新生鼠死亡和器官肿大，但不会影响尾骨数量。值得注意的是，尽管神经胚形成前后的 Dox 处理仍会导致新生鼠死亡，但不会导致 iLin28a Tg 新生鼠的器官肿大或尾骨数量增加。
神经胚形成期间 Lin28a 表达的时间调节会影响小鼠的发育事件，如轴向伸长的停止和胚胎生长。
