title: Local application of neurotrophins specifies axons through inositol 1,4,5-trisphosphate, calcium, and Ca2+/calmodulin-dependent protein kinases.
abstract: Neurons are highly polarized cells that have structurally distinct processes-the axons and dendrites-that differentiate from common immature neurites. In cultured hippocampal neurons, one of these immature neurites stochastically initiates rapid extension and becomes an axon, whereas the others become dendrites. Various extracellular and intracellular signals contribute to axon specification; however, the specific intracellular pathways whereby particular extracellular stimuli lead to axon specification remain to be delineated. Here, we found that the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) were required for axon specification in an autocrine or a paracrine fashion. Using local application with a micropipette to selectively stimulate individual neurites, we found that stimulation of a selected neurite by BDNF or NT-3 induced neurite outgrowth and subsequent axon formation. NT-3 induced a rapid increase in calcium ions (Ca(2+)) in an inositol 1,4,5-trisphosphate (IP(3))-dependent fashion as well as local activation of the Ca(2+) effector Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK) in the growth cone. Inhibition of neurotrophin receptors or CaMKK attenuated NT-3-induced axon specification in cultured neurons and axon formation in cortical neurons in vivo. These results identify a role for IP(3)-Ca(2+)-CaMKK signaling in axon specification.
authors.affiliation: 1Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakamuta
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Funahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Namba
authors.forename: Nariko
authors.initials: N
authors.lastname: Arimura
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tokumitsu
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Soderling
authors.forename: Akira
authors.initials: A
authors.lastname: Sakakibara
authors.forename: Takaki
authors.initials: T
authors.lastname: Miyata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kamiguchi
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D002478:Cells, Cultured; D020439:Growth Cones / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000378:metabolism*; D051381:Rats
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; C518911:neurotropin 3, mouse; D015544:Inositol 1,4,5-Trisphosphate; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002118:Calcium