Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Curr Biol. 2011 Dec 20;21(24):2033-45. doi: 10.1016/j.cub.2011.10.054. Epub 2011 Dec 1.
Biological timing mechanisms that integrate cyclical and successive processes are not well understood. C. elegans molting cycles involve rhythmic cellular and animal behaviors linked to the periodic reconstruction of cuticles. Molts are coordinated with successive transitions in the temporal fates of epidermal blast cells, which are programmed by genes in the heterochronic regulatory network. It was known that juveniles molt at regular 8-10 hr intervals, but the anticipated pacemaker had not been characterized.
We find that inactivation of the heterochronic gene lin-42a, which is related to the core circadian clock gene PERIOD (PER), results in arrhythmic molts and continuously abnormal epidermal stem cell dynamics. The oscillatory expression of lin-42a in the epidermis peaks during the molts. Further, forced expression of lin-42a leads to anachronistic larval molts and lethargy in adults.
Our results suggest that rising and falling levels of LIN-42A allow the start and completion, respectively, of larval molts. We propose that LIN-42A and affiliated factors regulate molting cycles in much the same way that PER-based oscillators drive rhythmic behaviors and metabolic processes in mature mammals. Further, the combination of reiterative and stage-specific functions of LIN-42 may coordinate periodic molts with successive development of the epidermis.
生物计时机制整合了周期性和连续性的过程，但尚未得到很好的理解。秀丽隐杆线虫的蜕皮周期涉及到有节奏的细胞和动物行为，这些行为与周期性的表皮角质层重建有关。蜕皮与表皮成胞细胞（blast cells）的时间命运的连续转变相协调，这些命运是由异时性调控网络中的基因编程的。已知幼虫每隔 8-10 小时定期蜕皮，但预期的起搏器尚未被描述。
我们发现，异时性基因 lin-42a 的失活，它与核心生物钟基因 PERIOD（PER）有关，导致无节奏的蜕皮和持续异常的表皮干细胞动力学。lin-42a 在表皮中的振荡表达在蜕皮期间达到峰值。此外，lin-42a 的强制表达导致幼虫蜕皮提前和成年后嗜睡。
我们的结果表明，LIN-42A 的水平上升和下降分别允许幼虫蜕皮的开始和完成。我们提出，LIN-42A 和相关因素以与成熟哺乳动物中基于 PER 的振荡器驱动节律行为和代谢过程大致相同的方式调节蜕皮周期。此外，LIN-42 的重复和阶段特异性功能的组合可能协调周期性蜕皮与表皮的连续发育。
