biostudies-literatureUltanir SKNIBIB NIH HHSHoward Hughes Medical InstituteNCRR NIH HHSNIMH NIH HHSNINDS NIH HHSNIGMS NIH HHS1127-42https://www.ebi.ac.uk/biostudies/studies/S-EPMC3333840biostudies-literatureUnknown73(6)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.NeuronChemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 Uncovers their roles in dendrite arborization and spine development.PMC3333840R01 MH077694R01 EB001987R01EB001987R01 MH084234-08R37 NS040929RR001614P41 RR001614P41 GM103481S10 RR0158045R01MH084234R01 MH084234RR015804R37NS040929R01 MH066084Li GUltanir SKBurlingame ALHertz NTJan LYPleasure SJGe WPShokat KMJan YNfalseChemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 Uncovers their roles in dendrite arborization and spine development.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.2012-01-01T00:00:00Z2012 Mar2020-10-29T12:02:19Z2019-03-27T00:52:34ZS-EPMC33338402244534110.1016/j.neuron.2012.01.019