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It has been well established that adult neurons in the CNS undergo little or no regeneration following insults while developing neurons are capable of extensive growth, extension and reorganization. Understanding the molecular mechanisms underlying neuronal plasticity during the course of normal development may therefore provide insights into the mechanisms that restrict regeneration of adult neurons. The neuronal remodeling events that occur during the development of the Drosophila mushroom body (MB) are initiated by axon pruning of γ-neurons, followed by axon re-extention to form adult specific connections. Only the γ-neurons in the developing MB undergo remodeling while others do not, offering a unique system in which axon re-growth can be distinguished from axon growth per se.
A MARCM forward genetic screen using piggyBac insertional mutagenesis has identified the orphan nuclear receptor, hormone receptor 51 (Hr51), as a key regulator of axon re-extension. We have shown that γ-neurons homozygous mutant for Hr51 extend axons normally in larvae, and undergo axon pruning at early pupa, yet fail to re-extend their axons to the adult specific connection. Later born neurons, also homozygous for the mutant allele, extend axons normally, indicating that the mutation affects axon re-extension and not axon growth per se. Genetic in vivo interaction experiments revealed that Hr51 can repress the expression of EcRB1. Interestingly, we also found that E75, a nuclear receptor that is regulated by EcRB1, is required for axon re-extension. Because the mammalian orthologs of Hr51 and E75 (NR2E3 and NR1D1, respectively) were shown to function together in several cases, our data supports that E75 and Hr51 may work together as heterodimers to induce axon regrowth following pruning. Our study has shown that the hormone receptors Hr51 and E75 may play a role in switching the growth status of axons from pruning to extension and that crosstalk between E75/Hr51 and EcRB1 may regulate different steps of neuronal remodeling. Understanding the mechanisms by which this network of nuclear receptors regulates neuronal remodeling may provide insights into the mechanisms that restrict regeneration of adult neurons in the CNS.