Epidermal and ECM Damage Following Pinch Injury Restricts Dendrite Regeneration in Drosophila

Neuronal dendrites can be injured by a number of insults, but the cellular mechanism by which dendrites respond to tissue injury and undergo repair is poorly understood. Much of the field's progress has evaluated dendrite regeneration following laser injury. While precise, laser injury does not accurately model the real-world damage to surrounding tissue that would accompany neuronal injury. Here, we modify a pinch injury technique to injure both the dendrites and their surrounding tissues in Drosophila melanogaster larvae, more similar to what is observed in real-world injury. We refined this technique such that only half of a sensory neuron's dendrites are injured, leaving the other half uninjured. Our data indicate that both dynamic and stable dendritic arbors regrow dendrites following pinch injury. Neurons primarily engage in compensatory regeneration whereby new branches are added on the uninjured half of the arbor. Comparing the regenerative response following pinch versus laser injury revealed that dendrites preferentially regrew into areas where the surrounding tissue was left intact, and not into areas where the surrounding tissue was damaged by pinch. These results prompted us to evaluate the damage sustained to surrounding tissue. In examining non-neuronal tissues after pinch injury, we found damage to epidermal cells and the ECM, but not glia. We also observed a robust immune response on the pinched half of the arbor. We conclude that the sustained damage to surrounding tissue and the initiation of an immune response create a non-permissive environment for dendrite regeneration following pinch injury.

Neuronal dendrites are injured in clinical conditions, such as stroke, traumatic brain injury, and neonatal hypoxia. Dendrites also degenerate in the early stages of a number of neurodegenerative diseases. The role of surrounding tissues in dendrite regeneration is poorly characterized, especially considering that neuronal injury is typically accompanied by broad tissue damage. Our data evaluates dendrite regeneration following an injury that better mirrors real-world conditions and demonstrates that broad tissue damage diminishes a neuron's capacity to regenerate its dendrites. Our findings show that neurons preferentially regrow into intact, undamaged tissue environments, addressing a large gap in the field's knowledge: how damage to the surrounding tissue limits neuron regeneration after injury.