Interplay between axonal Wnt5-Vang and dendritic Wnt5-Drl/Ryk signaling controls glomerular patterning in the Drosophila antennal lobe

Abstract

Despite the importance of dendritic targeting in neural circuit assembly, the mechanisms by which it is controlled still remain incompletely understood. We previously showed that in the developing Drosophila antennal lobe, the Wnt5 protein forms a gradient that directs the~45r otation of a cluster of projection neuron (PN) dendrites, including the adjacent DA1 and VA1d dendrites. We report here that the Van Gogh (Vang) transmembrane planar cell polarity (PCP) protein is required for the rotation of the DA1/VA1d dendritic pair. Cell type-specific rescue and mosaic analyses showed that Vang functions in the olfactory receptor neurons (ORNs), suggesting a codependence of ORN axonal and PN dendritic targeting. Loss of Vang suppressed the repulsion of the VA1d dendrites by Wnt5, indicating that Wnt5 signals through Vang to direct the rotation of the DA1 and VA1d glomeruli. We observed that the Derailed (Drl)/Ryk atypical receptor tyrosine kinase is also required for the rotation of the DA1/VA1d dendritic pair. Antibody staining showed that Drl/Ryk is much more highly expressed by the DA1 dendrites than the adjacent VA1d dendrites. Mosaic and epistatic analyses showed that Drl/Ryk specifically functions in the DA1 dendrites in which it antagonizes the Wnt5-Vang repulsion and mediates the migration of the DA1 glomerulus towards Wnt5. Thus, the nascent DA1 and VA1d glomeruli appear to exhibit Drl/Ryk-dependent biphasic responses to Wnt5. Our work shows that the final patterning of the fly olfactory map is the result of an interplay between ORN axons and PN dendrites, wherein converging preand postsynaptic processes contribute key Wnt5 signaling components, allowing Wnt5 to orient the rotation of nascent synapses through a PCP mechanism.

RYK-mediated filopodial pathfinding facilitates midgut elongation

“…Moreover, mathematical modeling establishes that the level of apoptosis measured experimentally in the epithelium can fully account for the observed differences in the elongation rate of Ryk −/− midgut epithelial tubes. Given that RYK is well documented to act in a cell-autonomous manner (Hing et al, 2020;Kim et al, 2019;Roy et al, 2018;Tourette et al, 2014;Zhong et al, 2011), these data together strongly suggest that RYK function is crucial in the epithelium during Phase I midgut elongation.…”

ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes

“…The three Drosophila RYK family members are Derailed (Drl), Drl-2 and Doughnut on 2 (Dnt). They play key roles in neuronal pathway selection (Callahan et al, 1995;Inaki et al, 2007) and muscle attachment site targeting (Callahan et al, 1996;Lahaye et al, 2012;Yoshikawa et al, 2001), as well as other aspects of fly nervous system function, including synaptic growth (Liebl et al, 2008), olfactory system patterning (Hing et al, 2020;Sakurai et al, 2009;Wu et al, 2014), mushroom body development (Reynaud et al, 2015), and peripheral nervous system wiring (Yasunaga et al, 2015). Both ROR and RYK families of receptors are thought to be regulated by the Drosophila WNT-5 ortholog, DWnt-5 (Lahaye et al, 2012;Ripp et al, 2018;Wouda et al, 2008;Yoshikawa et al, 2003).…”

Extrinsic Factors Regulating Dendritic Patterning

“…Dendritic targeting to discrete glomeruli is likely achieved by a combination of two mechanisms: gradients of diffusible morphogens might act in long-range to pattern glomeruli while contact-dependent adhesive or repulsive cues match PN dendrites to ORN axons. During development, multiple ligands are secreted by ORNs and form gradients along dorsolateral-ventromedial (DL-VM) axis in the antennal lobe ( Figure 2D ; Sweeney et al, 2011 ; Wu et al, 2014 ; Hing et al, 2020 ) while different types of PN dendrites expressing distinct levels of receptors to generate quantitative signaling to orient PN dendritic innervations. In addition, class-specific surface proteins or receptors potentially refine specific glomerular targeting locally via short-range contact-mediated action ( Figure 2C ; Hong et al, 2009 , 2012 ; Ward et al, 2015 ; Xie et al, 2019 ).…”

“…Moreover, an ORN axon-derived transmembrane planar cell polarity (PCP) protein, Van Gogh (Vang), serves as a mediator of Wnt5 repulsion in the context of PN dendritic targeting. Interestingly, PN dendrites express different levels of Drl (a Wnt5 receptor) to antagonize the Wnt5-Vang repulsion and direct appropriate localization to glomerular positions ( Wu et al, 2014 ; Hing et al, 2020 ). By utilizing combinatorial molecular codes both locally and globally, proper dendritic patterns can be established among distinct PN types, permitting appropriate synapse formation with partner ORNs to create an accurate olfactory map.…”