Dynamic properties of the segmentation clock mediated by microRNA.

Somites are embryonic precursors that give rise to the axial skeleton and skeletal muscles and form the segmental vertebrate body plan. Somitogenesis is controlled by the "segmentation clock", which contains multiple oscillator genes that must be tightly regulated at both the transcriptional and post-transcriptional levels for proper clock function. However, how the segmentation clock governs the formation of the somites at post-transcriptional level, remains unclear. In this work, we develop an integrated model with three modules for the segmentation clock and explore the mechanism for somite segmentation based on the dynamics of the network. By numerical simulations, we find that the amplitude and period of the somite segmentation clock are sensitive to Notch activity, which is fine-tuned by Lunatic fringe (Lfng) and microRNA (miRNA), and Lfng and miRNA are essential for forming the proper segmentation during somitogenesis. Moreover, miRNA is found to have a crucial role in minimizing the fluctuation period and amplitude to maintain coherent oscillation. Introduction of stochasticity in the model enables us to explain the available experimental data with dampening of oscillations. These findings uncover a fresh mechanism for regulation of the segmentation clock at a post-transcriptional level and provide important insights into how the relatively subtle effects of miRNAs on target genes can have broad effects in developmental situations that have critical requirements for tight posttranscriptional regulation.