A non-autonomous function of the core PCP protein VANGL2 directs peripheral axon turning in the developing cochlea

Ghimire, Satish R.; Ratzan, Evan M.; Deans, Michael R.

doi:10.1242/dev.159012

Cited by 28 publications

(47 citation statements)

References 74 publications

(144 reference statements)

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“…FZD and VANGL2 regulation of filopodial dynamics in the growth cone (Onishi et al, 2013) indicates that this is a cell-autonomous mechanism. In contrast, VANGL2 acts non-cell-autonomously to guide the peripheral axon of Type II spiral ganglion neurons (SGNs) in the cochlea (Ghimire et al, 2018). FZD3 and CELSR also act noncell-autonomously to promote the formation of long axon tracks (Morello et al, 2015;Feng et al, 2016); however, this does not require VANGL1/2 (Qu et al, 2014) and suggests that an intact intercellular PCP complex is not required for all axon guidance events.…”

Section: Introductionmentioning

confidence: 99%

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Frizzled3andFrizzled6Cooperate withVangl2to Direct Cochlear Innervation by Type II Spiral Ganglion Neurons

Ghimire

Deans

2019

J. Neurosci.

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Type II spiral ganglion neurons provide afferent innervation to outer hair cells of the cochlea and are proposed to have nociceptive functions important for auditory function and homeostasis. These neurons are anatomically distinct from other classes of spiral ganglion neurons because they extend a peripheral axon beyond the inner hair cells that subsequently makes a distinct 90 degree turn toward the cochlear base. As a result, patterns of outer hair cell innervation are coordinated with the tonotopic organization of the cochlea. Previously, it was shown that peripheral axon turning is directed by a nonautonomous function of the core planar cell polarity (PCP) protein VANGL2. We demonstrate using mice of either sex that Fzd3 and Fzd6 similarly regulate axon turning, are functionally redundant with each other, and that Fzd3 genetically interacts with Vangl2 to guide this process. FZD3 and FZD6 proteins are asymmetrically distributed along the basolateral wall of cochlear-supporting cells, and are required to promote or maintain the asymmetric distribution of VANGL2 and CELSR1. These data indicate that intact PCP complexes formed between cochlear-supporting cells are required for the nonautonomous regulation of axon pathfinding. Consistent with this, in the absence of PCP signaling, peripheral axons turn randomly and often project toward the cochlear apex. Additional analyses of Porcn mutants in which WNT secretion is reduced suggest that noncanonical WNT signaling establishes or maintains PCP signaling in this context. A deeper understanding of these mechanisms is necessary for repairing auditory circuits following acoustic trauma or promoting cochlear reinnervation during regenerationbased deafness therapies.

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Section: Introductionmentioning

confidence: 99%

“…In the developing cochlea, VANGL2 ensures that the peripheral axons of Type II SGNs complete a 90°turn toward the cochlear base before innervating the outer hair cells (OHCs) (Ghimire et al, 2018). SGNs are bipolar relay neurons that convey auditory information and consist of two major subtypes.…”

Section: Introductionmentioning

confidence: 99%

Frizzled3andFrizzled6Cooperate withVangl2to Direct Cochlear Innervation by Type II Spiral Ganglion Neurons

Ghimire

Deans

2019

J. Neurosci.

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“…Both proteins also have well-documented cell non-autonomous functions. Vertebrate Vangl2 acts as a ligand to steer migrating neurons (41, 42). We and others have shown that Drl could sequester Wnt5 using its extracellular Wnt Inhibitory Factor (WIF) motif (38, 43–45).…”

Section: Discussionmentioning

confidence: 99%

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

Hing

Snyder

Reger

et al. 2019

Preprint

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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 ~45° rotation 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 pre- and postsynaptic processes contribute key Wnt5 signaling components, allowing Wnt5 to orient the rotation of nascent synapses through a PCP mechanism.

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“…In both systems, the perception of sensory information depends upon mechanosensory transduction by hair cells (HCs) and the delivery of this information to the primary afferent neurons that make synaptic connections with the receptor cells (Lewis, Leverenz, & Bialek, ). Many research groups have investigated how classic axon guidance factors impact afferent innervation of the auditory and vestibular organs (Appler & Goodrich, ; Battisti, Fantetti, Moyers, & Fekete, ; Coate, Spita, Zhang, Isgrig, & Kelley, ; Defourny et al, ; Fekete & Campero, ; Frank & Goodrich, ; Ghimire, Ratzan, & Deans, ).…”

Section: Introductionmentioning

confidence: 99%

“…Many research groups have investigated how classic axon guidance factors impact afferent innervation of the auditory and vestibular organs (Appler & Goodrich, 2011;Battisti, Fantetti, Moyers, & Fekete, 2014;Coate, Spita, Zhang, Isgrig, & Kelley, 2015;Defourny et al, 2013;Fekete & Campero, 2007;Frank & Goodrich, 2018;Ghimire, Ratzan, & Deans, 2018).…”

Section: Introductionmentioning

confidence: 99%

Expression of class III Semaphorins and their receptors in the developing chicken (Gallus gallus) inner ear

Scott¹,

Jia²,

Biesemeier³

et al. 2019

J of Comparative Neurology

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Class III Semaphorin (Sema) secreted ligands are known to repel neurites expressing Neuropilin (Nrp) and/or Plexin (Plxn) receptors. There is, however, a growing body of literature supporting that Sema signaling also has alternative roles in development such as synaptogenesis, boundary formation, and vasculogenesis. To evaluate these options during inner ear development, we used in situ hybridization or immunohistochemistry to map the expression of Sema3D, Sema3F, Nrp1, Nrp2, and PlxnA1 in the chicken (Gallus gallus) inner ear from embryonic day (E)5–E10. The resulting expression patterns in either the otic epithelium or its surrounding mesenchyme suggest that Sema signaling could be involved in each of the varied functions reported for other tissues. Sema3D expression flanking the sensory tissue in vestibular organs suggests that it may repel Nrp2‐ and PlxnA1‐expressing neurites of the vestibular ganglion away from nonsensory epithelia, thus channeling them into the sensory domains at E5–E8. Expression of Sema signaling genes in the sensory hair cells of both the auditory and vestibular organs on E8–E10 may implicate Sema signaling in synaptogenesis. In the nonsensory regions of the cochlea, Sema3D in the future tegmentum vasculosum opposes Nrp1 and PlxnA1 in the future cuboidal cells; the abutment of ligand and receptors in adjacent domains may enforce or maintain the boundary between them. In the mesenchyme, Nrp1 colocalized with capillary‐rich tissue. Sema3D immediately flanks this Nrp1‐expressing tissue, suggesting a role in endothelial cell migration towards the inner ear. In summary, Sema signaling may play multiple roles in the developing inner ear.

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A non-autonomous function of the core PCP protein VANGL2 directs peripheral axon turning in the developing cochlea

Cited by 28 publications

References 74 publications

Frizzled3andFrizzled6Cooperate withVangl2to Direct Cochlear Innervation by Type II Spiral Ganglion Neurons

Frizzled3andFrizzled6Cooperate withVangl2to Direct Cochlear Innervation by Type II Spiral Ganglion Neurons

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

Expression of class III Semaphorins and their receptors in the developing chicken (Gallus gallus) inner ear

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