Journal
NEURON
Volume 73, Issue 6, Pages 1127-1142Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2012.01.019
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Funding
- National Institutes of Health (NIH) [NCRR RR015804, NCRR RR001614, NCRR01614, R37NS040929, 5R01MH084234, RO1EB001987]
- Howard Hughes Medical Institute
- National Alliance of Schizophrenia and Depression (NARSAD)
- Human Frontiers Science Programfellowship
- Genentech
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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.
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