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

Abstract

Secondary palate formation is a complex process that is frequently disturbed in mammals, resulting in the birth defect cleft palate. Gene targeting has identified components of cytokine/growth factor signalling systems such as Tgf-alpha/Egfr, Eph receptors B2 and B3 (Ephb2 and Ephb3, respectively), Tgf-beta2, Tgf-beta3 and activin-betaA (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 kinases (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 mice and the role of a Drosophila melanogaster Ryk orthologue, Derailed, in the transduction of repulsive axon pathfinding cues, 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.

IRF6, RYK, and PAX9 Expression in Facial Tissue of Children with Cleft Palate

“…Although essential for the morphogenesis of craniofacial structures, Ryk has not been extensively studied in the context of CBCLP. Protein localization studies and in situ hybridization have indicated that Ryk is broadly expressed in both the embryo and adult, and mouse embryos deficient in Ryk have craniofacial defects, including complete clefts, as well as skeletal defects (Halford et al, 2000). In this study, RYK expression was downregulated in CBCLP tissue compared to control tissue, providing evidence for the involvement of Ryk in the pathogenesis of CBCLP.…”

Axon guidance at the midline choice point

“…Since a likely mammalian homolog of Drl, referred to as RYK (Hovens et al, 1992), is expressed in the developing rat CNS (Kamitori et al, 1999), it is tempting to speculate that this unique RPTK also plays a significant role in regulating axon guidance in the developing vertebrate CNS. However, no pathfinding defects were reported in the recent characterization of RYK null mice (Halford et al, 2000). Nevertheless, the craniofacial abnormalities observed in these mice, as well as the finding that RYK exists in a complex with EphB2 and EphB3, suggest a role for RYK in Eph receptor-mediated signaling.…”

Transcriptional modulation of TCR, Notch and Wnt signaling pathways in SEB-anergized CD4+ T cells

“…37 Ephrin B3, a receptor tyrosine kinase, whose message was detected only in anergic cells (Table 5) might also be linked to the Wnt signaling pathway via its described ability to bind and phosphorylate a small receptor tyrosine kinase known as Ryk. 62 Ryk has been shown to act as a Wnt receptor and to bind specifically the mouse Fzd8 cysteine-rich domain. 63 How Ephrins might regulate the Wnt pathway is currently unknown.…”