Abstract
Segmentation in vertebrates first arises when the unsegmented paraxial mesoderm subdivides to form paired epithelial spheres called somites1,2. The Notch signalling pathway is important in regulating the formation and anterior–posterior patterning of the vertebrate somite3,4,5,6,7. One component of the Notch signalling pathway in Drosophila is the fringe gene, which encodes a secreted signalling molecule required for activation of Notch during specification of the wing margin8,9,10,11. Here we show that mice homozygous for a targeted mutation of the lunatic fringe (Lfng) gene, one of the mouse homologues12,13 of fringe, have defects in somite formation and anterior–posterior patterning of the somites. Somites in the mutant embryos are irregular in size and shape, and their anterior–posterior patterning is disturbed. Marker analysis revealed that in the presomitic mesoderm of the mutant embryos, sharply demarcated domains of expression of several components of the Notch signalling pathway are replaced by even gradients of gene expression. These results indicate that Lfng encodes an essential component of the Notch signalling pathway during somitogenesis in mice.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Keynes, R. J. & Stern, C. D. Mechanisms of vertebrate segmentation. Development 103, 413–429 (1988).
Gossler, A. & Hrabé de Angelis, M. Somitogenesis. Curr. Top. Dev. Biol. 38, 225–287 (1997).
Hrabé de Angelis, M., McIntyre II, J. & Gossler, A. Maintenance of somite borders in mice requires the Delta homologue Dll1. Nature 386, 717–721 (1997).
Jen, W.-C., Wettstein, D., Turner, D., Chitnis, A. & Kintner, C. The Notch ligand, X-Delta-2, mediates segmentation of the paraxial mesoderm in Xenopus embryos. Development 124, 1169–1178 (1997).
Saga, Y., Hata, N., Koseki, H. & Taketo, M. M. Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev. 11, 1827–1839 (1997).
Wong, . C. et al. Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm. Nature 387, 288–292 (1997).
Shen, J. et al. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell 89, 629–639 (1997).
Irvine, K. D. & Wieschaus, E. fringe, a boundary-specific signaling molecule, mediates interactions between dorsal and ventral cells during Drosophila wing development. Cell 79, 595–606 (1994).
Fleming, R. J., Gu, Y. & Hukriede, N. A. Serrate-mediated activation of Notch is specifically blocked by the product of the gene fringe in the dorsal compartment of the Drosophila wing imaginal disc. Development 124, 2973–2981 (1997).
Panin, V. M., Papayannopoulos, V., Wilson, R. & Irvine, K. D. Fringe modulates Notch-ligand interactions. Nature 387, 908–912 (1997).
Blair, S. S. Limb development: Marginal Fringe benefits. Curr. Biol. 7, R686–R690 (1997).
Cohen, B. et al. Fringe boudnaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila. Nature Genet. 16, 283–288 (1997).
Johnston, S. H. et al. Afamily of mammalian fringe genes implicated in boundary determination and the Notch pathway. Development 124, 2245–2254 (1997).
Tannahill, D., Cook, G. M. W. & Keynes, R. J. Axon guidance and somites. Cell Tissue Res. 290, 275–283 (1997).
Montarras, D. et al. Developmental patterns in the expression of Myf5, MyoD, myogenin, and MRF4 during myogenesis. New Biol. 3, 592–600 (1991).
Candia, A. F. et al. Mox-1 and Mox-2 define a novel homeobox gene subfamily and are differentially expressed during early mesodermal patterning in mouse embryos. Development 116, 1123–1136 (1992).
Neubüser, A., Koseki, H. & Balling, R. Characterization and developmental expression of Pax9, a paired-box-containing gene related to Pax1. Dev. Biol. 170, 701–16 (1995).
Neidhardt, L. M., Kispert, A. & Herrmann, B. G. Amouse gene of the paired-related homeobox class expressed in the caudal somite compartment and in the developing vertebral column, kidney and nervous system. Dev. Genes Evol. 207, 330–339 (1997).
Evrard, Y. A., Lun, Y., Aulehla, A., Gan, L. & Johnson, R. L. lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394, 377–381 (1998).
Dunwoodie, S. L., Henrique, D., Harrison, S. M. & Beddington, R. S. Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 124, 3065–3076 (1997).
1. Bettenhausen, B., Hrabe de Angelis, M., Simon, D., Guenet, J.-L. & Gossler, A. Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila Delta. Development 121, 2407–2418 (1995).
Mitsiadis, T. A., Henrique, D., Thesleff, I. & Lendahl, U. Mouse Serrate-1 (Jagged1): Expression in the developing tooth is regulated by epithelial–mesenchymal interactions and fribroblast growth factor-4. Development 124, 1473–1483 (1997).
de Celis, J. F., Garcia-Bellido, A. & Bray, S. J. Activation and function of Notch at the dorsal–ventral boundary of the wing imaginal disc. Development 122, 359–369 (1996).
Doherty, D., Feger, G., Younger-Shepherd, S., Jan, L. Y. & Jan, Y. N. Delta is a ventral to dorsal signal complementary to Serrate, another Notch ligand, in Drosophila wing formation. Genes Dev. 10, 421–434 (1996).
Swiatek, P. & Gridley, T. Perinatal lethality and defects in hindbrain devleopment in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev. 2071–2084 (1993).
Wilkinson, D. G. in In Situ Hybridization: A Practical Approach (ed. Wilkinson, D. G.) 75–83 (IRL, Oxford, 1992).
Martin, J. F., Bradley, A. & Olson, E. N. The paired-like homeobox gene MHox is required for early events of skeletogenesis in multiple lineages. Genes Dev. 9, 1237–1249 (1995).
Acknowledgements
We thank R. Johnson for exchanging unpublished data; C. Norton for doing the blastocyst injections; A. Gossler, R. Jiang and T. O'Brien for comments on the manuscript; and R. Balling, R.Beddington, A. Gossler, B. Hermann, E. Olson and C. Wright for probes. This work was supported by grants from the NIH and the March of Dimes Foundation to T.G., and by a grant from the National Cancer Institute to The Jackson Laboratory.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhang, N., Gridley, T. Defects in somite formation in lunatic fringe-deficient mice. Nature 394, 374–377 (1998). https://doi.org/10.1038/28625
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/28625
This article is cited by
-
Nr6a1 controls Hox expression dynamics and is a master regulator of vertebrate trunk development
Nature Communications (2022)
-
Notch signaling pathway: architecture, disease, and therapeutics
Signal Transduction and Targeted Therapy (2022)
-
Coupling delay controls synchronized oscillation in the segmentation clock
Nature (2020)
-
Lunatic Fringe is a potent tumor suppressor in Kras-initiated pancreatic cancer
Oncogene (2016)
-
On the origin of vertebrate somites
Zoological Letters (2015)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.