Abstract
Secondary palate formation is a complex process that is frequently disturbed in mammals, resulting in the birth defect cleft palate1,2. Gene targeting has identified components of cytokine/growth factor signalling systems such as Tgf-α/Egfr, Eph receptors B2 and B3 (Ephb2 and Ephb3, respectively), Tgf-β2, Tgf-β3 and activin-βA (ref. 3) as regulators of secondary palate development. Here we demonstrate that the mouse orphan receptor ‘related to tyrosine kinases’ (Ryk) is essential for normal development and morphogenesis of craniofacial structures including the secondary palate. Ryk belongs to a subclass of catalytically inactive, but otherwise distantly related, receptor protein tyrosine kinases4,5,6 (RTKs). Mice homozygous for a null allele of Ryk have a distinctive craniofacial appearance, shortened limbs and postnatal mortality due to feeding and respiratory complications associated with a complete cleft of the secondary palate. Consistent with cleft palate phenocopy in Ephb2/Ephb3-deficient mice7 and the role of a Drosophila melanogaster Ryk orthologue, Derailed, in the transduction of repulsive axon pathfinding cues8,9, our biochemical data implicate Ryk in signalling mediated by Eph receptors and the cell-junction–associated Af-6 (also known as Afadin). Our findings highlight the importance of signal crosstalk between members of different RTK subfamilies.
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Acknowledgements
We thank P. Mountford for the IRES. βgeo.pA cassette; staff in the LICR Animal Facility for animal husbandry; V. Feaks and G. Brown for histology; G.-F. Tu for DNA sequencing; and H. Cooper and A. Dunn for comments on the manuscript. This study was supported in part by a NH&MRC project grant and by the Cooperative Research Centre for Cellular Growth Factors. M.M.H. is a recipient of an Australian Postgraduate Research Award and M.L.H. is a recipient of a Senior Research Fellowship from the Australian Research Council.
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Halford, M., Armes, J., Buchert, M. et al. Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nat Genet 25, 414–418 (2000). https://doi.org/10.1038/78099
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DOI: https://doi.org/10.1038/78099
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