title: Ryk, a receptor regulating Wnt5a-mediated neurogenesis and axon morphogenesis of ventral midbrain dopaminergic neurons.
abstract: Ryk is an atypical transmembrane receptor tyrosine kinase that has been shown to play multiple roles in development through the modulation of Wnt signaling. Within the developing ventral midbrain (VM), Wnts have been shown to contribute to the proliferation, differentiation, and connectivity of dopamine (DA) neurons; however, the Wnt-related receptors regulating these events remain less well described. In light of the established roles of Wnt5a in dopaminergic development (regulating DA differentiation as well as axonal growth and repulsion), and its interaction with Ryk elsewhere within the central nervous system, we investigated the potential role of Ryk in VM development. Here we show temporal and spatial expression of Ryk within the VM, suggestive of a role in DA neurogenesis and axonal plasticity. In VM primary cultures, we show that the effects of Wnt5a on VM progenitor proliferation, DA differentiation, and DA axonal connectivity can be inhibited using an Ryk-blocking antibody. In support, Ryk knockout mice showed reduced VM progenitors and DA precursor populations, resulting in a significant decrease in DA cells. However, Ryk(-/-) mice displayed no defects in DA axonal growth, guidance, or fasciculation of the MFB, suggesting other receptors may be involved and/or compensate for the loss of this receptor. These findings identify for the first time Ryk as an important receptor for midbrain DA development.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
authors.forename: Brette D
authors.initials: BD
authors.lastname: Blakely
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Bye
authors.forename: Chathurini V
authors.initials: CV
authors.lastname: Fernando
authors.forename: Asheeta A
authors.initials: AA
authors.lastname: Prasad
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.forename: Maria L
authors.initials: ML
authors.lastname: Macheda
authors.forename: Steven A
authors.initials: SA
authors.lastname: Stacker
authors.forename: Clare L
authors.initials: CL
authors.lastname: Parish
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D059290:Dopaminergic Neurons / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D046509:Tissue Culture Techniques; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C118148:Ryk protein, mouse