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Regeneration in the adult Drosophila brain

Crocker, K.L., Marischuk, K., Rimkus, S.A., Zhou, H., Yin, J.C.P., Boekhoff-Falk, G.

Preprint posted on January 16, 2020 https://www.biorxiv.org/content/10.1101/2020.01.16.908640v1

A hidden stem cell-like population found in the Drosophila brain: let's regenerate.

Selected by Ivana Viktorinová

Introduction

Traumatic brain injury has serious consequences in humans and limitations for full injury repair exist. Understanding the molecular mechanism underlying neuronal regeneration has been subject of extensive investigations. Although our human brain stops to make new neurons shortly after birth, there are indications that our brain may have capacity to regenerate even later in life. This is based on recent findings in rodents, where two brain regions are capable to generate various neuronal cell types. This hope is great, but how to regenerate other brain parts? To transplant progenitor stem cells into the human brain is one option, but still remains a challenge. Thus, new ways are intensively sought.

 

In this work, the authors used fruit flies (Drosophila melanogaster) as a model. It shares many similarities with human brain physiology (e.g. synapse and neuronal activity) and good knowledge about neural development in Drosophila exists. But, as the authors point, there seems to be a knowledge gap in our understanding as to how brain behaves after traumatic brain injury (what is the damage response?). The authors focus on investigation after the adult Drosophila brain injury, which leads them to intriguing findings.

 

Author’s Findings

 

To understand regeneration in the brain after a traumatic brain injury, the authors first establish a reproducible method termed the penetrating small targeted area of the brain (STAB) injury in Drosophila brains. They employed a thin insect metal needle to injure young and adult Drosophila brains. They specifically targeted the mushroom body (MB), a region that is required for learning and memory in the Drosophila brain. The particular reason for this choice is that this brain part can be easily accessed for microscopic imaging and MB’s neuroblasts show the longest proliferation activity than the other brain regions.

 

After applying STAB method, the authors uncovered an interesting difference between injury of young and adult Drosophila brains shortly after the brain injury. There was almost no impact found on the animal survival within next post-injury 24h in young animals in contrast to the older adults. This suggested that younger animals might have display higher regenerative potential. In general, based on mitotic markers, the authors found increased cell proliferation in the injury location and also around this location accompanied by transient cell death (with the highest peak after injury and indistinguishable from the same-aged uninjured brains after 10 days).

 

In accordance with the above findings, the authors further show that cell proliferation ability decreases with age and is highest for adults in a short time frame of 7 days after adult eclosion (pupa to adult transition). Further analysis of this work showed that proliferating cells differentiate to both glia and neurons (new axon tracks were also detected).

 

Based on neural progenitor proteins and transcripts (e.g. deadpan and asense) detection, the authors uncovered neuronal differentiation during and later after brain injury. This finding indicated that neuroblast-like cell population, which was activated or generated straight after the brain injury. These cells represent up to now unknow cell types in the Drosophila brain. The authors further questioned whether these cells were newly generated/dedifferentiated glial cells after the brain injury or whether there was a quiescent population of stem-like cells. Based on cell lineage-tracking technique, the authors showed that it was the latter case and that these were stem (neuroblast) cell-like cells, often also accompanied by cells with Deadpan- and Asense- positive cells near the injury.

 

Using MARCM clonal system (permanently labeling dividing cells), the authors then detected regeneration that did not only happen in the injured location but also in other neighboring brain regions, suggesting a potential structural repair in the whole post-injury brain. Finally, they found that the injury did impact locomotor circuit function. Based on fly behavior, this was repaired at later points (14 days) after the injury.

 

The authors conclude and emphasize that similar hidden cells, which are capable of regeneration, may exist in human brains. If so, this may serve to screen for pharmacological agents and find novel therapeutic approaches for human neuroregenerative diseases and brain injuries.

What I like about it

The authors successfully established a new STAB method and elegantly combined it with other several genetic tools that exist for well-established Drosophila model. I like that the authors were not afraid to  investigate an injured tissue and looked at the brain regeneration from a different point of view.

In addition, fruit fly belongs to one of the most favorable models in biological research to elucidate basics of complex processes in vertebrates (where investigations are limited). As Drosophilist, it makes me always happy to hear about discoveries, which can be analyzed on the most simplest basic level in this tiny model and provide new views for the vertebrate research.

I hope that their future experiments will help to elucidate hidden and unknown complex processes in vertebrate/humans brain regeneration.

 

Questions:

1) Based on your experiment, it looks like the mechanical stress triggers regeneration. Have you perhaps tried to activate this hidden population by other physical means e.g. precise laser ablations instead of only the STAB method?

2) Have you tried to STAB target also other brain regions than the MB to try to localize the most regeneration potent cells in the Drosophila brain?

 

Posted on: 12th February 2020

doi: https://doi.org/10.1242/prelights.16846

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