AXON RE-EXTENSION

The molecular mechanisms of axon re-extension following developmental axon pruning

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 Obiettivo del progetto (Objective)

'Lack of neuronal regeneration following injury such as spinal cord injury is the major cause for poor functional recovery. It has long been appreciated that young neurons can grow, undergo reorganization and synapse on appropriate targets during development while adult neurons cannot, however the molecular basis of these differences remain unclear. Studying the molecular mechanisms that regulate axon re-extension following remodeling during development holds the promise to uncover molecular rules underlying this phenomena and are therefore of great potential. A model system that allows a unique molecular exploration of axon re-extension is that of axon pruning in Drosophila. Pruning is a process in which neurons first extend excessive branches, later prune away inappropriate ones with precise spatial and temporal control and, at least in the some cases, re-extend their axons to form mature connections. Pruning was found to essential for sculpting the mature nervous systems of vertebrates and invertebrates. During my post-doctoral studies, I performed a mosaic screen and identified a mutant exhibiting normal pruning but lacking the stereotypical axon re-extension that follows. Remarkably, other neurons, belonging to the mutant clone but which do not undergo pruning, extend their axons normally at the same developmental time, indicating that the mutation selectively affected axon re-extension following pruning but not axon extension per se. This novel finding suggests that there is molecular switch dedicated to changing the growing status of a neuron. The causal gene was mapped to an uncharacterized steroid hormone receptor, HR51. Here, I propose to characterize the role of HR51 in axon re-extension as well as identify its ligand. In addition I propose to perform a suppressor screen directed at identifying additional molecules involved in axon re-extension. Taken together, these three aims should provide insight into the molecular mechanisms of axon re-extension.'

Introduzione (Teaser)

Scientists have long known that lack of neuronal regeneration after a spinal cord injury is the major reason for poor functional recovery. An EU-funded project is investigating whether axons have the potential for regeneration and what mechanisms are involved.

Descrizione progetto (Article)

To investigate this issue, researchers with the AXON RE-EXTENSION project. Studied the fruit fly, Drosophila. Axon pruning, also called degeneration, is the process in which neurons extend excessive branches and then discard inappropriate ones with precise temporal and spatial control. In some cases, neurons re-extend their axons to form the mature nervous system. Pruning occurs in both vertebrates and invertebrates.

In Drosophila, scientists found a mutant that allowed neurons to undergo pruning but not axon regeneration. Interestingly, other neurons belonging to the mutant clone did not undergo pruning, but did extend their axons. This finding suggests that there is a molecular switch responsible for changing the neuron's growing status. A steroid hormone, HR51, also known as UNF, was identified as the possible switch.

Following this discovery, the researchers established that Hr51/UNF is required for axon growth of particular structures in the Drosophila's brain called mushroom body (MB) gamma neurons following pruning but not for their initial axon outgrowth. To distinguish these two processes, the former was termed developmental axon regrowth.

Furthermore, Hr51/UNF can inhibit the expression of the receptor responsible for pruning, suggesting that to activate axon regrowth, it may be necessary to inactivate the pruning function. Researchers then found another receptor,E75, that works with Hr51/UNF to spur developmental axon regeneration.

These findings suggest that the combined action of Hr51/UNF and E75 represents a new developmental programme required for switching the growth of axons from degeneration to regeneration. Additional research has been funded to further understand the differences among initial growth, developmental regrowth, and regeneration following injury.

This work is a breakthrough in our understanding of axon regeneration. In the future, it may mean that people with spinal injuries can walk again.