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The E3 ubiquitin ligase Mycbp2 genetically interacts with Robo2 to modulate axon guidance in the mouse olfactory system

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Abstract

The E3 ubiquitin ligase Mycbp2 and it homologues play an important role in axon guidance and synaptogenesis in Drosophila, Caenorhabditis elegans, zebrafish and mouse. Despite this conserved function, the molecular and cellular basis of Mycbp2-dependent axon guidance remains largely unclear. We have examined here the effect of the loss-of-MYCBP2 function on the topography of the olfactory sensory neuron projection from the nasal cavity to the olfactory bulb in mice. A subpopulation of olfactory sensory axons failed to project to the dorsal surface of the olfactory bulb causing abnormal topography in this neural pathway. These defects were similar to the olfactory bulb phenotype in loss-of-ROBO2 function mice. While mice heterozygous for either Mycbp2 or Robo2 were normal, mice double heterozygous for these two genes produced severe defects in the olfactory system. Therefore, Mycbp2 and Robo2 were found to cooperate within a genetic network that has profound effects on axon guidance. The Mycbp2 phenotype could be partly explained by aberrant patterning of olfactory sensory neurons residing in the dorsal compartment of the nasal cavity. Some of these neurons fail to appropriately express Robo2 which is consistent with their aberrant projection to the ventral olfactory bulb. These results provide the first evidence linking an ubiquitin ligase to an axon guidance receptor during pathfinding in the developing mammalian nervous system.

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Acknowledgments

We would like to thank Julie Conway for taking care of our animal colonies, Timothy O’Brien for providing the Mycbp2274−4 and the Mycbp215DttMb mice, Aaron Diantonio for the Mycbp2∆8−9 mice, William Andrews for the Robo2Del5 mice and Peter Mombaerts for the P2-IRES-Tau-LacZ mice. This work was supported by grants to BK from the National Health and Medical Research Council of Australia.

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The authors declare no competing financial interests.

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Authors and Affiliations

  1. Brain Growth and Regeneration Lab, School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia

    G. James, B. Key & A. Beverdam

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  1. G. James
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  2. B. Key
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  3. A. Beverdam
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Correspondence to B. Key.

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B. Key and A. Beverdam equally contributed to this work.

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James, G., Key, B. & Beverdam, A. The E3 ubiquitin ligase Mycbp2 genetically interacts with Robo2 to modulate axon guidance in the mouse olfactory system. Brain Struct Funct 219, 861–874 (2014). https://doi.org/10.1007/s00429-013-0540-8

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  • DOI: https://doi.org/10.1007/s00429-013-0540-8

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