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PMID:16631377

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Citation

Antar, LN, Li, C, Zhang, H, Carroll, RC and Bassell, GJ Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol. Cell. Neurosci. 32:37-48

Abstract

Genetic deficiency of the mRNA binding protein FMRP results in the most common inherited form of mental retardation, Fragile X syndrome. We investigated the localization and function of FMRP during development of hippocampal neurons in culture. FMRP was distributed within granules that extended into developing axons and growth cones, detectable at distances over 300 microm from the cell body. In mature cultures, FMRP granules were present in both axons and dendrites, with pockets of higher concentrations appearing intermittently, along distal axon segments and near synapses. MAP1b mRNA, a known FMRP target, was also localized to axon growth cones. Morphometric analysis of growth cones from the FMR1 KO revealed both excess filopodia and reduced motility. At later stages during synapse formation, FMR1 KO neurons exhibited excessive filopodia and long spines along dendrites, yet there was a marked decrease in the density of spine-like protrusions juxtaposed to presynaptic terminals. In contrast, there was no difference in the density of shaft synapses between FMR1 KO and WT. Brief depolarization of WT neurons resulted in increased numbers of filopodia and spine synapses, whereas no additional morphologic changes were observable in dendrites of FMR1 KO neurons that already had increased density of filopodia-spines. These findings suggest that alterations in the regulation of axonal growth and innervation in FMR1 KO neurons may contribute to the dendritic and spine pathology in Fragile X syndrome. This work has broader implications for understanding the role of mRNA binding proteins in developmental and protein-synthesis-dependent plasticity.

Links

PubMed Online version:10.1016/j.mcn.2006.02.001

Keywords

Animals; Animals, Newborn; Cell Differentiation/physiology; Cell Movement/physiology; Cells, Cultured; Cytoplasmic Granules/metabolism; Cytoplasmic Granules/ultrastructure; Dendritic Spines/metabolism; Dendritic Spines/pathology; Dendritic Spines/ultrastructure; Female; Fragile X Mental Retardation Protein/genetics; Fragile X Mental Retardation Protein/metabolism; Fragile X Syndrome/genetics; Fragile X Syndrome/metabolism; Fragile X Syndrome/pathology; Growth Cones/metabolism; Growth Cones/pathology; Growth Cones/ultrastructure; Hippocampus/abnormalities; Hippocampus/growth & development; Hippocampus/pathology; Male; Mice; Mice, Knockout; Microtubule-Associated Proteins/genetics; Pseudopodia/metabolism; Pseudopodia/pathology; Pseudopodia/ultrastructure; RNA, Messenger/metabolism; Synapses/metabolism; Synapses/pathology; Synapses/ultrastructure; Synaptic Transmission/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:FMR1

located_in

GO:0045202: synapse

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

located_in

GO:1902737: dendritic filopodium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

located_in

GO:1990812: growth cone filopodium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

located_in

GO:0030424: axon

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

located_in

GO:0043197: dendritic spine

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

located_in

GO:0030425: dendrite

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

located_in

GO:0032433: filopodium tip

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:FMR1

involved_in

GO:0060998: regulation of dendritic spine development

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FMR1

involved_in

GO:0051489: regulation of filopodium assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FMR1

part_of

GO:0045202: synapse

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

involved_in

GO:0060998: regulation of dendritic spine development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FMR1

part_of

GO:1902737: dendritic filopodium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

part_of

GO:0030425: dendrite

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

part_of

GO:0043197: dendritic spine

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

part_of

GO:1990812: growth cone filopodium

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

part_of

GO:0032433: filopodium tip

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

part_of

GO:0030424: axon

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FMR1

involved_in

GO:0051489: regulation of filopodium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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