Abstract
Dendrite arborization and synapse formation are essential for wiring the neural circuitry. The evolutionarily conserved NDR1/2 kinase pathway, important for polarized growth from yeast to mammals, controls dendrite growth and morphology in the worm and fly. The function of NDR1/2 in mammalian neurons and their downstream effectors were not known. Here we show that the expression of dominant negative (kinase-dead) NDR1/2 mutants or siRNA increase dendrite length and proximal branching of mammalian pyramidal neurons in cultures and in vivo, whereas the expression of constitutively active NDR1/2 has the opposite effect. Moreover, NDR1/2 contributes to dendritic spine development and excitatory synaptic function. We further employed chemical genetics and identified NDR1/2 substrates in the brain, including two proteins involved in intracellular vesicle trafficking: AAK1 (AP-2 associated kinase) and Rabin8, a GDP/GTP exchange factor (GEF) of Rab8 GTPase. We finally show that AAK1 contributes to dendrite growth regulation, and Rabin8 regulates spine development.
Copyright © 2012 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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Age Factors
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Animals
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Animals, Newborn
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Autoantigens / metabolism
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Cells, Cultured
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Dendrites / ultrastructure*
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Dendritic Spines / physiology*
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Electroporation
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Embryo, Mammalian
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Gene Expression Regulation, Developmental / genetics*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism*
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Hippocampus / cytology
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Humans
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Membrane Proteins / metabolism
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Mice
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Microtubule-Associated Proteins
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Models, Biological
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Models, Molecular
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Mutation / genetics
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Neurons / cytology*
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Neurons / physiology
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Patch-Clamp Techniques
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Phosphorylation / genetics
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rats
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Rats, Long-Evans
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Synapses / genetics
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Synapses / physiology
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Transfection
Substances
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Autoantigens
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Golgin subfamily A member 2
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Guanine Nucleotide Exchange Factors
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MAP2 protein, rat
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Membrane Proteins
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Microtubule-Associated Proteins
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RNA, Small Interfering
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Green Fluorescent Proteins
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AAK1 protein, rat
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Ndr2 protein, rat
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Ndrg1 protein, rat
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Protein Serine-Threonine Kinases