Modifying transcript lengths of cycling mouse segmentation genes.

Regular production of somites, precursors of the axial skeleton and attached muscles is controlled by a molecular oscillator, the segmentation clock, which drives cyclic transcription of target genes in the unsegmented presomitic mesoderm (PSM). The clock is based on a negative feedback loop which generates pulses of transcription that oscillate with the same periodicity as somite formation. Mutants in several oscillating genes including the Notch pathway gene Lunatic fringe (Lfng) and the Notch target Hes7, result in defective somitogenesis and disorganised axial skeletons. Both genes encode negative regulators of Notch signalling output, but it is not yet clear if they are just secondary clock targets or if they encode components of a primary, pacemaker oscillator. In this paper, we try to identify components in the primary oscillator by manipulating delays in the feedback circuitry. We characterise recombinant mice in which Lfng and Hes7 introns are lengthened in order to delay mRNA production. Lengthening the third Hes7 intron by 10 or 20 kb disrupts accurate RNA splicing and inactivates the gene. Lfng expression and activity is normal in mice whose Lfng is lengthened by 10 kb, but no effects on segmentation are evident. We discuss these results in terms of the relative contributions of transcriptional and post-transcriptional delays towards defining the pace of segmentation, and of alternative strategies for manipulating the period of the clock.

Stauber M ，Laclef C ，Vezzaro A ，Page ME ，Ish-Horowicz D ... -  《-》

Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock.

Dale JK ，Maroto M ，Dequeant ML ，Malapert P ，McGrew M ，Pourquie O ... -  《NATURE》

Notch is a critical component of the mouse somitogenesis oscillator and is essential for the formation of the somites.

Ferjentsik Z ，Hayashi S ，Dale JK ，Bessho Y ，Herreman A ，De Strooper B ，del Monte G ，de la Pompa JL ，Maroto M ... -  《PLoS Genetics》

3'-UTR-dependent regulation of mRNA turnover is critical for differential distribution patterns of cyclic gene mRNAs.

Somite segmentation, a prominent periodic event in the development of vertebrates, is instructed by cyclic expression of several genes, including Hes7 and Lunatic fringe (Lfng). Transcriptional regulation accounts for the cyclic expression. In addition, because the expression patterns vary in a cycle, rapid turnover of mRNAs should be involved in the cyclic expression, although its contribution remains unclear. Here, we demonstrate that 3'-UTR-dependent rapid turnover of Lfng and Hes7 plays a critical role in their dynamic expression patterns. The regions active in the transcription of Lfng and Hes7 are wholly overlapped in the posterior presomitic mesoderm (PSM) of the mouse embryo. However, their distribution patterns are slightly different; Hes7 mRNA shows a broader distribution pattern than Lfng mRNA in the posterior PSM. Lfng mRNA is less stable than Hes7 mRNA, where their 3'-UTRs are responsible for the different stability. Using transgenic mice expressing Venus under the control of the Hes7 promoter, which leads to cyclic transcription in the PSM, we reveal that the Lfng 3'-UTR provides the narrow distribution pattern of Lfng mRNA, whereas the Hes7 3'-UTR contributes the relatively broad distribution pattern of Hes7 mRNA. Thus, we conclude that 3'-UTR-dependent mRNA stability accounts for the differential distribution patterns of Lfng and Hes7 mRNA. Our findings suggest that 3'-UTR-dependent regulation of mRNA turnover plays a crucial role in the diverse patterns of mRNA distribution during development.

Nitanda Y ，Matsui T ，Matta T ，Higami A ，Kohno K ，Nakahata Y ，Bessho Y ... -  《-》

Negative feedback loop formed by Lunatic fringe and Hes7 controls their oscillatory expression during somitogenesis.

Chen J ，Kang L ，Zhang N 《GENESIS》