Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment.
ATP7A is a P-type ATPase that transports copper from cytosol into the secretory pathway for loading onto cuproproteins or efflux. Mutations in Atp7a cause Menkes disease, a copper-deficiency disorder fatal in the postnatal period due to severe neurodegeneration. Early postnatal copper injections are known to diminish degenerative changes in some human patients and mice bearing mutations in Atp7a. In situ hybridization studies previously demonstrated that ATP7A transcripts are expressed widely in the brain. ATP7A-specific antibody was used to study the neurodevelopmental expression and localization of ATP7A protein in the mouse brain. Based on immunoblot analyses, ATP7A expression is most abundant in the early postnatal period, reaching peak levels at P4 in neocortex and cerebellum. In the developing and adult brain, ATP7A levels are greatest in the choroid plexus/ependymal cells of the lateral and third ventricles. ATP7A expression decreases in most neuronal subpopulations from birth to adulthood. In contrast, ATP7A expression increases in CA2 hippocampal pyramidal and cerebellar Purkinje neurons. ATP7A is expressed in a subset of astrocytes, microglia, oligodendrocytes, tanycytes and endothelial cells. ATP7A is largely localized to the trans-Golgi network, adopting the cell-specific and developmentally-regulated morphology of this organelle. The presence of ATP7A in the axons of postnatal, but not adult, optic nerve suggests stage-specific roles for this enzyme. In sum, the precisely-regulated neurodevelopmental expression of ATP7A correlates well with the limited therapeutic window for effective treatment of Menkes disease.
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MJ
University of Connecticut Health Center, Department of Neuroscience, Academic Research Building (E)-4047, 263 Farmington Avenue, Farmington, CT 06030, USA.
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El Meskini
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Ronnett
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Mains
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D000251:Adenosine Triphosphatases / Q000096:biosynthesis*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000096:biosynthesis*; D000073840:Copper-Transporting ATPases; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism
C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases