Abstract
The molecular pathways controlling cerebellar Purkinje cell dendrite formation and maturation are poorly understood. The Purkinje cell degeneration (pcd) mutant mouse is characterized by mutations in Nna1, a gene discovered in an axonal regenerative context, but whose actual function in development and disease is unknown. We found abnormal development of Purkinje cell dendrites in postnatal pcd(Sid) mice and linked this deficit to a deletion mutation in exon 7 of Nna1. With single cell gene profiling and virus-based gene transfer, we analyzed a molecular pathway downstream to Nna1 underlying abnormal Purkinje cell dendritogenesis in pcd(Sid) mice. We discovered that mutant Nna1 dramatically increases intranuclear localization of lysyl oxidase propeptide, which interferes with NF-κB RelA signaling and microtubule-associated protein regulation of microtubule stability, leading to underdevelopment of Purkinje cell dendrites. These findings provide insight into Nna1's role in neuronal development and why its absence renders Purkinje cells more vulnerable.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Behavior, Animal
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Cells, Cultured
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Cerebellum / cytology
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Cerebellum / pathology
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Dendrites / pathology
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Dendrites / physiology*
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Disease Models, Animal
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Exons / genetics
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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Gene Expression Profiling
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Gene Expression Regulation / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Motor Activity / genetics
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Mutation / genetics
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NF-kappa B / metabolism*
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Nerve Degeneration / genetics
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Nerve Degeneration / pathology
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Nerve Degeneration / physiopathology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Oligonucleotide Array Sequence Analysis / methods
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Organ Culture Techniques
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Phosphopyruvate Hydratase / metabolism
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Protein-Lysine 6-Oxidase / genetics
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Protein-Lysine 6-Oxidase / metabolism*
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Psychomotor Performance / physiology
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Purkinje Cells / cytology*
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Purkinje Cells / pathology
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RNA Interference / physiology
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Serine-Type D-Ala-D-Ala Carboxypeptidase / genetics
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Serine-Type D-Ala-D-Ala Carboxypeptidase / metabolism*
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Signal Transduction / physiology*
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Time Factors
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Transduction, Genetic / methods
Substances
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NF-kappa B
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Nerve Tissue Proteins
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Protein-Lysine 6-Oxidase
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Serine-Type D-Ala-D-Ala Carboxypeptidase
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Agtpbp1 protein, mouse
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GTP-Binding Proteins
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Phosphopyruvate Hydratase