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J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/08/657/13 $2.00
Volume 138, Number 3, August 11, 1997 657-669

Suppression of KIF2 in PC12 Cells Alters the Distribution of a Growth Cone Nonsynaptic Membrane Receptor and Inhibits Neurite Extension

Gerardo Morfini,* Santiago Quiroga,Dagger Alberto Rosa,Dagger Kenneth Kosik,§ and Alfredo Cáceres*

* Instituto Investigación Médica Mercedes y Martín Ferreyra, 5000 Córdoba, Argentina; Dagger  Departamento Química Biológica, Facultad Ciencias Químicas (CIQUIBIC) Universidad Nacional de Córdoba/CONICET, 5000 Córdoba, Argentina; and § Department of Neurology (Neuroscience), Harvard Medical School and Center for Neurological Diseases, Department of Medicine (Division of Neurology), Brigham and Women's Hospital, Boston, Massachusetts 02115

In the present study, we present evidence about the cellular functions of KIF2, a kinesin-like superfamily member having a unique structure in that its motor domain is localized at the center of the molecule (Noda Y., Y. Sato-Yoshitake, S. Kondo, M. Nangaku, and N. Hirokawa. 1995. J. Cell Biol. 129:157-167.). Using subcellular fractionation techniques, isopicnic sucrose density centrifugation of microsomal fractions from developing rat cerebral cortex, and immunoisolation with KIF2 antibodies, we have now identified a type of nonsynaptic vesicle that associates with KIF2. This type of organelle lacks synaptic vesicle markers (synapsin, synaptophysin), amyloid precursor protein, GAP-43, or N-cadherin. On the other hand, it contains beta gc, which is a novel variant of the beta  subunit of the IGF-1 receptor, which is highly enriched in growth cone membranes. Both beta gc and KIF2 are upregulated by NGF in PC12 cells and highly concentrated in growth cones of developing neurons. We have also analyzed the consequences of KIF2 suppression by antisense oligonucleotide treatment on nerve cell morphogenesis and the distribution of synaptic and nonsynaptic vesicle markers. KIF2 suppression results in a dramatic accumulation of beta gc within the cell body and in its complete disappearance from growth cones; no alterations in the distribution of synapsin, synaptophysin, GAP-43, or amyloid percursor protein are detected in KIF2-suppressed neurons. Instead, all of them remained highly enriched at nerve terminals. KIF2 suppression also produces a dramatic inhibition of neurite outgrowth; this phenomenon occurs after beta gc has disappeared from growth cones. Taken collectively, our results suggest an important role for KIF2 in neurite extension, a phenomenon that may be related with the anterograde transport of a type of nonsynaptic vesicle that contains as one of its components a growth cone membrane receptor for IGF-1, a growth factor implicated in nerve cell development.


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