The Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2.

The Wnt signaling pathways control many critical developmental and adult physiological processes. In vertebrates, one fundamentally important function of Wnts is to provide directional information by regulating the evolutionarily conserved planar cell polarity (PCP) pathway during embryonic morphogenesis. However, despite the critical roles of Wnts and PCP in vertebrate development and disease, little is known about the molecular mechanisms underlying Wnt regulation of PCP. Here, we have found that the receptor-like tyrosine kinase (Ryk), a Wnt5a-binding protein required in axon guidance, regulates PCP signaling. We show that Ryk interacts with Vangl2 genetically and biochemically, and such interaction is potentiated by Wnt5a. Loss of Ryk in a Vangl2(+/-) background results in classic PCP defects, including open neural tube, misalignment of sensory hair cells in the inner ear, and shortened long bones in the limbs. Complete loss of both Ryk and Vangl2 results in more severe phenotypes that resemble the Wnt5a(-/-) mutant in many aspects such as shortened anterior-posterior body axis, limb, and frontonasal process. Our data identify the Wnt5a-binding protein Ryk as a general regulator of the mammalian Wnt/PCP signaling pathway. We show that Ryk transduces Wnt5a signaling by forming a complex with Vangl2 and that Ryk regulates PCP by at least in part promoting Vangl2 stability. As human mutations in WNT5A and VANGL2 are found to cause Robinow syndrome and neural tube defects, respectively, our results further suggest that human mutations in RYK may also be involved in these diseases.

Behavioral characterization of escalated aggression induced by GABA(B) receptor activation in the dorsal raphe nucleus.

RATIONALE: Pharmacological activation of GABA(B) receptors in the dorsal raphe nucleus (DRN) can escalate territorial aggression in male mice. OBJECTIVES: We characterized this escalated aggression in terms of its behavioral and environmental determinants. METHODS: Aggressive behavior of resident male (CFW or ICR mouse) was assessed in confrontations with a group-housed intruder. Either baclofen (0.06 nmol/0.2 µl) or vehicle (saline) was microinjected into the DRN 10 min before the confrontation. We examined baclofen-heightened aggression in five situations: aggression in a neutral arena and after social instigation (experiment 1), aggression during the light phase of the cycle (experiment 2), aggression without prior fighting experience (experiment 3), aggression toward a female (experiment 4), and aggression after defeat experiences (experiment 5). In addition, we examined the body targets towards which bites are directed and the duration of aggressive bursts after baclofen treatment. RESULTS: Regardless of the past social experience, baclofen escalated aggressive behaviors. Even in the neutral arena and after defeat experiences, where aggressive behaviors were inhibited, baclofen significantly increased aggression. Baclofen increased attack bites directed at vulnerable body areas of male intruders but not toward a female and only in the dark. Also, baclofen prolonged the duration of aggressive bursts. CONCLUSIONS: For baclofen to escalate aggression, specific stimulation (male intruder) and tonic level of serotonin (dark cycle) are required. Once aggressive behavior is triggered, intra-DRN baclofen escalates the level of aggression to abnormal levels and renders it difficult to terminate. Also, baclofen counteracts the effects of novelty or past experiences of defeat.