Post‐transcriptional regulation of Lunatic fringe provides a critical mechanism to control Notch pathway signaling during somitogenesis

Abstract

Somites are the embryonic precursors of the vertebrae, ribs, and skeletal muscles. They form from the presomitic mesoderm (PSM) by a periodic segmentation process called somitogenesis. This process is controlled in part by a segmentation clock that utilizes oscillatory expression of genes such as Lunatic fringe (Lfng) to track temporal information. Lfng activity levels in the mouse or chick PSM oscillate with a period that matches the rate of somite formation, regulating the timing of somitogenesis. Lfng encodes a fucose‐specific beta1,3 N‐acetylglucosaminyltransferase that modifies the extracellular domain of Notch receptors. This modification affects Notch activation, suggesting that oscillatory LFNG activity could regulate cyclic Notch pathway activity in the PSM. Thus, many models suggest that the oscillation of the Lfng glycosyltransferase activity underlies the coordinated, cyclic activation of the Notch pathway during somitogenesis. For such rapid oscillations to play a functional role during development, stable clock function requires that tight transcriptional control of Lfng expression be coupled with mechanisms that confer short half‐lives to the Lfng RNA transcript, and to the LFNG protein activity. We have examined post‐transcriptional mechanisms that may regulate Lfng activity within the segmentation clock. We will discuss miRNA‐based mechanisms that regulate mRNA transcript stability, as well as post‐translational mechanisms that control protein activity turnover.