title: β-III spectrin is critical for development of purkinje cell dendritic tree and spine morphogenesis.
abstract: Mutations in the gene encoding β-III spectrin give rise to spinocerebellar ataxia type 5, a neurodegenerative disease characterized by progressive thinning of the molecular layer, loss of Purkinje cells and increasing motor deficits. A mouse lacking full-length β-III spectrin (β-III⁻/⁻) displays a similar phenotype. In vitro and in vivo analyses of Purkinje cells lacking β-III spectrin, reveal a critical role for β-III spectrin in Purkinje cell morphological development. Disruption of the normally well ordered dendritic arborization occurs in Purkinje cells from β-III⁻/⁻ mice, specifically showing a loss of monoplanar organization, smaller average dendritic diameter and reduced densities of Purkinje cell spines and synapses. Early morphological defects appear to affect distribution of dendritic, but not axonal, proteins. This study confirms that thinning of the molecular layer associated with disease pathogenesis is a consequence of Purkinje cell dendritic degeneration, as Purkinje cells from 8-month-old β-III⁻/⁻ mice have drastically reduced dendritic volumes, surface areas and total dendritic lengths compared with 5- to 6-week-old β-III⁻/⁻ mice. These findings highlight a critical role of β-III spectrin in dendritic biology and are consistent with an early developmental defect in β-III⁻/⁻ mice, with abnormal Purkinje cell dendritic morphology potentially underlying disease pathogenesis.
authors.affiliation: Department of Neurology and Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: Gao
authors.forename: Emma M
authors.initials: EM
authors.lastname: Perkins
authors.forename: Yvonne L
authors.initials: YL
authors.lastname: Clarkson
authors.forename: Steven
authors.initials: S
authors.lastname: Tobia
authors.forename: Alastair R
authors.initials: AR
authors.lastname: Lyndon
authors.forename: Mandy
authors.initials: M
authors.lastname: Jackson
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D064026:Calbindins; D002540:Cerebral Cortex / Q000166:cytology* / Q000254:growth & development*; D003712:Dendrites / Q000648:ultrastructure*; D049229:Dendritic Spines / Q000378:metabolism*; D050581:Excitatory Amino Acid Transporter 4 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D028061:Phosphate Transport Proteins / Q000378:metabolism; D011689:Purkinje Cells / Q000166:cytology*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D016622:Silver Staining / Q000379:methods; D015222:Sodium Channels / Q000378:metabolism; D013049:Spectrin / Q000172:deficiency / Q000378:metabolism*; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D064026:Calbindins; D050581:Excitatory Amino Acid Transporter 4; D051273:Glucose Transporter Type 2; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D028061:Phosphate Transport Proteins; D064030:S100 Calcium Binding Protein G; C491046:Scn8a protein, mouse; C493465:Slc17a7 protein, mouse; C493390:Slc1a6 protein, mouse; C495682:Slc2a2 protein, mouse; D015222:Sodium Channels; D050598:Vesicular Glutamate Transport Protein 1; C410982:ank protein, mouse; D013049:Spectrin
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