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J Neurosci ; 34(15): 5342-54, 2014 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-24719112

RESUMEN

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 ß1-integrin to stimulate the PKC- and CaMKII-dependent activation of ß1-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 ß1-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.


Asunto(s)
Integrina beta1/metabolismo , Neuritas/metabolismo , Proteínas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Procesos de Crecimiento Celular , Células Cultivadas , Endosomas/metabolismo , Eliminación de Gen , Células HEK293 , Hipocampo/citología , Hipocampo/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Neuritas/efectos de los fármacos , Neuritas/fisiología , Células PC12 , Fosforilación , Unión Proteica , Transporte de Proteínas , Proteínas/genética , Ratas , Semaforina-3A/farmacología
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