Nerve processes are “lost” without SUMO protease

Precisely assembled nerve connections are a prerequisite for the proper functioning of the nervous system. We found that neurons lacking a novel SUMO (Small Ubiquitin-like MOdifier) protease were misrouted resulting in a disrupted neuronal map.

HFSP Long-Term Fellow Daniela Berdnik and colleagues
authored on Thu, 21 June 2012

The cellular mechanisms underlying neuronal connection specificity during the establishment of neuronal maps are largely unknown. To find novel molecules required for the neuronal map formation we used the well-characterized olfactory connections of the fly brain as a model and genetic techniques to label and manipulate single neurons. From a genetic screen, we discovered a novel SUMO protease required for the correct targeting of olfactory nerve extensions. In the mutant neurons, nerve processes seemed “lost” prompting us to give the gene the German name verloren (velo).

Figure: “Lost” neurites of a single velo mutant neuron (labeled in green) mistarget to inappropriate areas within the fly brain (synapses are shown in red) disrupting the olfactory map.

Sumoylation is a reversible post-translational modification controlling many biological processes. The small SUMO protein is attached to and detached from substrates altering their functions. SUMO proteases can act during SUMO maturation but also SUMO de-conjugation and thereby either promote or revert targeting and morphogenesis via the de-conjugation of SUMO protein(s). The catalytic domain is required for Velo’s function in neurons and the defects observed in velo mutants can be partially rescued by expressing two other SUMO proteases. Using sophisticated genetic tools, our study allowed specialized functions of these enzymes to be examined in vivo in postmitotic neurons that can be dissociated from its roles during neuronal proliferation and survival.

One of the future challenges will be to identify Velo target substrates. Because our tagged Velo transgene localizes to the nucleus the potential substrate is likely to be nuclear. Given the numerous studies about sumoylation regulating transcription and the fact that several transcription factors have been implicated in olfactory neuron target selection it will be interesting to investigate such candidates for their role as Velo substrates. Furthermore, sumoylation has been associated with several neurodegenerative diseases. Elucidating the function of Velo’s human ortholog in neurons will further our understanding of the role of sumoylation across species and furthermore emphasize the importance of specific posttranslational modifications during disease.

Reference

The SUMO Protease Verloren Regulates Dendrite and Axon Targeting in Olfactory Projection Neurons. Berdnik D, Favaloro V, Luo L. J Neurosci. 2012 Jun 13;32(24):8331-40. PMID: 22699913 [PubMed - in process]

Pubmed link