The serine/threonine kinase Ndr2 controls integrin trafficking and integrin-dependent neurite growth.
Integrins have been implicated in various processes of nervous system development, including proliferation, migration, and differentiation of neuronal cells. In this study, we show that the serine/threonine kinase Ndr2 controls integrin-dependent dendritic and axonal growth in mouse hippocampal neurons. We further demonstrate that Ndr2 is able to induce phosphorylation at the activity- and trafficking-relevant site Thr(788/789) of β1-integrin to stimulate the PKC- and CaMKII-dependent activation of β1-integrins, as well as their exocytosis. Accordingly, Ndr2 associates with integrin-positive early and recycling endosomes in primary hippocampal neurons and the surface expression of activated β1-integrins is reduced on dendrites of Ndr2-deficient neurons. The role of Ndr2 in dendritic differentiation is also evident in vivo, because Ndr2-null mutant mice show arbor-specific alterations of dendritic complexity in the hippocampus. This indicates a role of Ndr2 in the fine regulation of dendritic growth; in fact, treatment of primary neurons with Semaphorin 3A rescues Ndr2 knock-down-induced dendritic growth deficits but fails to enhance growth beyond control level. Correspondingly, Ndr2-null mutant mice show a Semaphorin 3A(-/-)-like phenotype of premature dendritic branching in the hippocampus. The results of this study show that Ndr2-mediated integrin trafficking and activation are crucial for neurite growth and guidance signals during neuronal development.
Department of Genetics and Molecular Neurobiology, Institute of Biology, and Institute for Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany, Department of Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany, Protein Engineering Group, Leibniz-Institute for Molecular Pharmacology, 13125 Berlin, Germany, Department of Auditory Learning and Speech, Leibniz-Institute for Neurobiology, 39118 Magdeburg, Germany, and Center for Behavioral Brain Sciences, 39106 Magdeburg, Germany.
Kati
K
Rehberg
Stefanie
S
Kliche
Deniz A
DA
Madencioglu
Marlen
M
Thiere
Bettina
B
Müller
Bernhard Manuel
BM
Meineke
Christian
C
Freund
Eike
E
Budinger
Oliver
O
Stork
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D048708:Cell Growth Processes; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism; D017353:Gene Deletion; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D040121:Semaphorin-3A / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D019012:Integrin beta1; C485172:Ndr2 protein, mouse; D011506:Proteins; D040121:Semaphorin-3A
dendritic and axonal growth; dendritic branching; integrin activation; integrin trafficking; mouse; serine/threonine kinase Ndr2