Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk

Secondary palate formation is a complex process that is frequently disturbe d in mammals, resulting in the birth defect cleft palate(1,2). Gene targeti ng has identified components of cytokine/growth factor signalling systems s uch as Tgf-alpha/Egfr, Eph receptors B2 and B3 (Ephb2 and Ephb3, respective ly), Tgf-beta 2, Tgf-beta 3 and activin-beta A (ref. 3) as regulators of se condary palate development, Here we demonstrate that the mouse orphan recep tor 'related to tyrosine kinases' (Ryk) is essential for normal development and morphogenesis of craniofacial structures including the secondary palat e. Ryk belongs to a subclass of catalytically inactive, but otherwise dista ntly related, receptor protein tyrosine kinases(4-6) (RTKs). Mice homozygou s for a null allele of Ryk have a distinctive craniofacial appearance, shor tened limbs and postnatal mortality due to feeding and respiratory complica tions associated with a complete cleft of the secondary palate. Consistent with cleft palate phenocopy in Ephb2/Ephb3-deficient mice(7) and the role o f a Drosophila melanogaster Ryk orthologue, Derailed, in the transduction o f repulsive axon pathfinding cues(8,9), 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.