Journal
MOLECULAR AND CELLULAR NEUROSCIENCE
Volume 34, Issue 3, Pages 409-421Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2006.11.018
Keywords
ATP7A; Menkes disease; olfactory system; olfactory sensory neurons; neurodevelopment; axonal outgrowth; synapse
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Funding
- NIDCD NIH HHS [R01 DC004736, DC-04736, R55 DC004736] Funding Source: Medline
- NIDDK NIH HHS [R01 DK032949, R56 DK032949, DK-32949, R37 DK032949] Funding Source: Medline
- NINDS NIH HHS [R01 NS039657, NS-41079, NS-39657, R01 NS041079] Funding Source: Medline
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Menkes disease (MD) is a neurodegenerative disorder caused by mutations in the copper transporter, ATP7A, a P-type ATPase. We previously used the olfactory system to demonstrate that ATP7A expression is developmentally, not constitutive, regulated, peaking during synaptogenesis when it is highly expressed in extending axons in a copper-independent manner. Although not known to be associated with axonal functions, we explored the possibility that the inability of mutant ATP7A to support axon outgrowth contributes to the neurodegeneration seen in MD. In vivo analysis of the olfactory system in mottled brindled (Atp7a(Mobr)) mice, a rodent model for MD, demonstrates that ATP7A deficiency affects olfactory sensory neuron (OSN) maturation. Disrupted OSN axonal projections and mitral/tufted cell dendritic growth lead to altered synapse integrity and glomerular disorganization in the olfactory bulbs of Atp7a(Mobr) mice. Our data indicate that the neuronal abnormalities observed in MD are a result of specific age-dependent developmental defects. This study demonstrates a role for ATP7A and/or copper in axon outgrowth and synaptogenesis, and will further help identify the cause of the neuropatbology that characterizes MD. (c) 2006 Elsevier Inc. All rights reserved.
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