The receptor tyrosine kinase Ror is required for dendrite regeneration in Drosophila neurons

Abstract

While many regulators of axon regeneration have been identified, very little is known about mechanisms that allow dendrites to regenerate after injury. Using a Drosophila model of dendrite regeneration, we performed a candidate screen of receptor tyrosine kinases (RTKs) and found a requirement for RTK-like orphan receptor (Ror). We confirmed that Ror was required for regeneration in two different neuron types using RNA interference (RNAi) and mutants. Ror was not required for axon regeneration or normal dendrite development, suggesting a specific role in dendrite regeneration. Ror can act as a Wnt coreceptor with frizzleds (fzs) in other contexts, so we tested the involvement of Wnt signaling proteins in dendrite regeneration. We found that knockdown of fz, dishevelled (dsh), Axin, and gilgamesh (gish) also reduced dendrite regeneration. Moreover, Ror was required to position dsh and Axin in dendrites. We recently found that Wnt signaling proteins, including dsh and Axin, localize microtubule nucleation machinery in dendrites. We therefore hypothesized that Ror may act by regulating microtubule nucleation at baseline and during dendrite regeneration. Consistent with this hypothesis, localization of the core nucleation protein γTubulin was reduced in Ror RNAi neurons, and this effect was strongest during dendrite regeneration. In addition, dendrite regeneration was sensitive to partial reduction of γTubulin. We conclude that Ror promotes dendrite regeneration as part of a Wnt signaling pathway that regulates dendritic microtubule nucleation.

Endosomal Wnt signaling proteins control microtubule nucleation in dendrites

“…We have recently shown that Patronin-mediated minus-end growth is an important regulator of dendritic microtubules in Drosophila [77], so it is possible that microtubule severing in conjunction with Patronin recruitment to minus ends can compensate for nucleation under most normal circumstances. Consistent with this hypothesis, phenotypes from reduction of nucleation or Patronin become more evident after severe stress, including axon [29] or dendrite [77,98] injury.…”

“…Modulating Wnt signaling could therefore influence neuroprotection in dendrites. In addition, we have found that this pathway is required during dendrite regeneration to position nucleation sites in regrowing dendrites [98]. Interestingly, G protein coupled receptors (GPCRs) represent 33% of all Food and Drug Administration-approved drug targets, and as part of this family, fz presents a possible target [82].…”

Kinetochore proteins suppress neuronal microtubule dynamics and promote dendrite regeneration

“…However, it was only recently shown that neurons survive removal of all dendrites and can regrow a new arbor ( Stone et al , 2014 ). Only a handful of genes including Akt ( Song et al , 2012 ) and Ror ( Nye et al , 2020 ) have been linked to dendrite regeneration. To identify dendritic RAGs, we isolated RNA from Drosophila neurons after in vivo dendrite removal.…”

Scrap and Build for Functional Neural Circuits: Spatiotemporal Regulation of Dendrite Degeneration and Regeneration in Neural Development and Disease

“…A recent study in Drosophila C4da neurons has identified the receptor tyrosine kinase-like orphan receptor (Ror) as a critical factor for dendrite regeneration after injury (Nye et al, 2020 ). Subsequent studies suggest that Ror promotes TM nucleation for dendritic branch growth in cooperation with the Wnt signaling pathway (Nye et al, 2020 ; Weiner et al, 2020 ).…”