Cdk5 Regulation of the GRAB-Mediated Rab8-Rab11 Cascade in Axon Outgrowth
Author
dc.contributor.author
Furusawa, Kotaro
Author
dc.contributor.author
Asada, Akiko
Author
dc.contributor.author
Urrutia, Pamela
Author
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González Billault, Christian
Author
dc.contributor.author
Fukuda, Mitsunori
Author
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Hisanaga, Shin-ichi
Admission date
dc.date.accessioned
2018-05-10T16:51:07Z
Available date
dc.date.available
2018-05-10T16:51:07Z
Publication date
dc.date.issued
2017
Cita de ítem
dc.identifier.citation
J. Neurosci., January 25, 2017, 37(4):790–806
es_ES
Identifier
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10.1523/JNEUROSCI.2197-16.2016
Identifier
dc.identifier.uri
https://repositorio.uchile.cl/handle/2250/147633
Abstract
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Neurons communicate with each other through their axons and dendrites. However, a full characterization of the molecular mechanisms
involved in axon and dendrite formation is still incomplete. Neurite outgrowth requires the supply of membrane components for surface
expansion. Two membrane sources for axon outgrowth are suggested: Golgi secretary vesicles and endocytic recycling endosomes. In
non-neuronal cells, trafficking of secretary vesicles from Golgi is regulated by Rab8, a member of Rab small GTPases, and that of recycling
endosomes is by Rab11, another member of Rabs. However, whether these vesicles are coordinately or independently transported in
growing axons is unknown. Herein, we find that GRAB, a guanine nucleotide exchange factor for Rab8, is a novel regulator of axon
outgrowth. Knockdown of GRAB suppressed axon outgrowth of cultured mouse brain cortical neurons. GRAB mediates the interaction
between Rab11A and Rab8A, and this activity is regulated by phosphorylation at Ser169 and Ser180 by Cdk5-p35. The nonphosphorylatable
GRAB mutant S169/180A promoted axonal outgrowth to a greater extent than did the phosphomimetic GRAB mutant S169/180D.
Phosphorylation of GRAB suppressed its guanine nucleotide exchange factor activity and its ability to recruit Rab8A- to Rab11A-positive
endosomes. In vivo function of GRAB and its Cdk5-phophorylation were shown in migration and process formation of developing
neurons in embryonic mouse brains. These results indicate that GRAB regulates axonal outgrowth via activation and recruitment of
Rab8A- to Rab11A-positive endosomes in a Cdk5-dependent manner.
es_ES
Patrocinador
dc.description.sponsorship
MEXT in Japan, 25290024, 26117004, 15H04367, 15H01198 /postdoctoral Fondecyt Grant
3160630 / Fondecyt 1140325 / FONDAP 15150012