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The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity

Abstract

The serially segmented (metameric) structures of vertebrates are based on somites that are periodically formed during embryogenesis. A ‘clock and wavefront’ model has been proposed to explain the underlying mechanism of somite formation1, in which the periodicity is generated by oscillation of Notch components (the clock) in the posterior pre-somitic mesoderm (PSM)2,3,4,5,6. This temporal periodicity is then translated into the segmental units in the ‘wavefront’7,8. The wavefront is thought to exist in the anterior PSM and progress backwards at a constant rate; however, there has been no direct evidence as to whether the levels of Notch activity really oscillate and how such oscillation is translated into a segmental pattern in the anterior PSM. Here, we have visualized endogenous levels of Notch1 activity in mice, showing that it oscillates in the posterior PSM but is arrested in the anterior PSM. Somite boundaries formed at the interface between Notch1-activated and -repressed domains. Genetic and biochemical studies indicate that this interface is generated by suppression of Notch activity by mesoderm posterior 2 (Mesp2) through induction of the lunatic fringe gene (Lfng). We propose that the oscillation of Notch activity is arrested and translated in the wavefront by Mesp2.

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Figure 1: Visualization of the Mesp2 protein and oscillation of Notch1 activity and Lfng transcripts.
Figure 2: Analyses of gene and protein expression critical for clock oscillation and its arrest.
Figure 3: Mesp2 may activate Lfng to arrest the oscillation of Notch activity in the anterior PSM.
Figure 4: Schematic representation of the regulatory mechanism underlying the clock system and of the implications of Mesp2 function in establishing the segmental boundary.

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Acknowledgements

We thank S. Kitajima and E. Ikeno for their assistance in generating the Mesp2–venus knock-in mouse; M. Ikumi and Y. Takahashi for technical assistance and maintaining the mice used in this study; A. Gossler and R. Johnson for providing the Dll1and lunatic fringe knockout mice; and H. Hamada for CYP26a-null embryos. We also thank H. Takeda for critical reading of this manuscript. We are grateful to H. Tanaka for preparing purified Mesp2 protein. This work was supported by Grants-in-Aid for Science Research on Priority Areas (B), the Organized Research Combination System and National BioResource Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Correspondence to Yumiko Saga.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Movie 1

Changes in the expression domain of Mesp2-venus. (MOV 3804 kb)

Supplementary Figures 1-3

A knock-in strategy to generate Mesp2-venus (Fig. 1); the change of expression pattern of Mesp2-venus in vivo (Fig, 2); and double fluorescent in situ hybridization for L-fng and Mesp2 (Fig. 3). (JPG 89 kb)

Supplementary Figure 4

L-fng expression and Notch activity oscillate in the posterior PSM, but do not arrest correctly in the anterior PSM in the absence of Mesp2. (JPG 149 kb)

Supplementary Figure 5 and 6

A schematic representation of the sequential changes in the expression patterns (Fig. 5); expression pattern of Mesp2 in CYP26a-null embryos (Fig. 6). (JPG 120 kb)

Supplementary Data

This document contains legends for Supplementary Movie 1 and Supplementary Figs 1-6, and Supplementary Methods and additional references. (DOC 27 kb)

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Morimoto, M., Takahashi, Y., Endo, M. et al. The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity. Nature 435, 354–359 (2005). https://doi.org/10.1038/nature03591

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