Author:

Keywords:

Animals, Cell Polarity, Gene Knockdown Techniques, Hippocampus, Membrane Proteins, Microtubule-Associated Proteins, Neurons, PC12 Cells, Phosphoproteins, Protein Kinase C, Rats, Receptors, Nerve Growth Factor, Stathmin, Tubulin, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, GLYCOGEN-SYNTHASE KINASE-3-BETA, TRANS-GOLGI NETWORK, KINASE-D, HIPPOCAMPAL-NEURONS, NERVOUS-SYSTEM, GROWING AXONS, IN-VIVO, INTRACELLULAR-LOCALIZATION, SECRETORY TRAFFICKING, PHOSPHORYLATION SITES, 03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences, 31 Biological sciences, 32 Biomedical and clinical sciences, 34 Chemical sciences

Abstract:

In order for neurons to perform their function, they must establish a highly polarized morphology characterized, in most of the cases, by a single axon and multiple dendrites. Herein we find that the evolutionarily conserved protein Kidins220 (kinase D-interacting substrate of 220-kDa), also known as ARMS (ankyrin repeat-rich membrane spanning), a downstream effector of protein kinase D and neurotrophin and ephrin receptors, regulates the establishment of neuronal polarity and development of dendrites. Kidins220/ARMS gain and loss of function experiments render severe phenotypic changes in the processes extended by hippocampal neurons in culture. Although Kidins220/ARMS early overexpression hinders neuronal development, its down-regulation by RNA interference results in the appearance of multiple longer axon-like extensions as well as aberrant dendritic arbors. We also find that Kidins220/ARMS interacts with tubulin and microtubule-regulating molecules whose role in neuronal morphogenesis is well established (microtubule-associated proteins 1b, 1a, and 2 and two members of the stathmin family). Importantly, neurons where Kidins220/ARMS has been knocked down register changes in the phosphorylation activity of MAP1b and stathmins. Altogether, our results indicate that Kidins220/ARMS is a key modulator of the activity of microtubule-regulating proteins known to actively regulate neuronal morphogenesis and suggest a mechanism by which it contributes to control neuronal development.