Mesp2 initiates somite segmentation through the Notch signalling pathway

Abstract

The Notch-signalling pathway is important in establishing metameric pattern during somitogenesis. In mice, the lack of either of two molecules involved in the Notch-signalling pathway, Mesp2 or presenilin-1 (Ps1), results in contrasting phenotypes: caudalized versus rostralized vertebra. Here we adopt a genetic approach to analyse the molecular mechanism underlying the establishment of rostro-caudal polarity in somites. By focusing on the fact that expression of a Notch ligand, Dll1, is important for prefiguring somite identity, we found that Mesp2 initiates establishment of rostro-caudal polarity by controlling two Notch-signalling pathways. Initially, Mesp2 activates a Ps1-independent Notch-signalling cascade to suppress Dll1 expression and specify the rostral half of the somite. Ps1-mediated Notch-signalling is required to induce Dll1 expression in the caudal half of the somite. Therefore, Mesp2- and Ps1-dependent activation of Notch-signalling pathways might differentially regulate Dll1 expression, resulting in the establishment of the rostro-caudal polarity of somites.

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Figure 1: Introduction of a lacZ reporter gene or activated Notch1 under the control of the Mesp2 promoter by homologous recombination (ac), lacZ expression in Mesp2-lacZ mouse embryos (dg) and a variation of Mesp2 expression domain in wild-type embryos (hk).
Figure 2: Expression of rostral somite markers at 11.5 d.p.c. Mesp2L/L and Psen1−/− embryos show distinct patterns of expression.
Figure 3: Schematic illustration of the expression pattern of Dll1 and segmentation of somites in the mouse embryo.
Figure 4: Expression patterns of caudal genes Dll1 and Uncx4.1 are correlated with skeletal morphology in various mutants.
Figure 5: Activated Notch1 alters the spatial pattern of Dll1 expression.
Figure 6: A hypothesis and a model for the regulation of Dll1 expression.
Figure 7: Both the Mesp2L/L and Psen1−/− mutants exhibit a reduced level of Notch signalling, and activated Notch1 in the Mesp2 locus activates Notch signalling.

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Acknowledgements

We thank R. Conlon (Notch1 cDNA), A. Gossler (Dll1 cDNA), P. Gruss (Uncx4.1 cDNA), R. Kageyama (Hes5 cDNA) and E.M. De Robertis (Cer1 cDNA) for providing reagents; and W. Murai, M. Ikumi, S. Sinzawa, M. Uchida and S. Takeda for technical assistance. This work was supported in part by Grants in Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture in Japan and Special Coordination Funds for Promoting Science and Technology to Y.S., and grants from the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Uehara Memorial Foundation and Ichiro Kanehara Foundation to H.K.

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Correspondence to Haruhiko Koseki or Yumiko Saga.

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Takahashi, Y., Koizumi, K., Takagi, A. et al. Mesp2 initiates somite segmentation through the Notch signalling pathway . Nat Genet 25, 390–396 (2000). https://doi.org/10.1038/78062

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