RT Journal Article
SR Electronic
T1 Cdk5 regulation of the GRAB-mediated Rab8-Rab11 cascade in axon outgrowth
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2197-16
DO 10.1523/JNEUROSCI.2197-16.2016
A1 Kotaro Furusawa
A1 Akiko Asada
A1 Pamela Urrutia
A1 Christian Gonzalez-Billault
A1 Mitsunori Fukuda
A1 Shin-ichi Hisanaga
YR 2016
UL http://www.jneurosci.org/content/early/2016/12/09/JNEUROSCI.2197-16.2016.abstract
AB 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 non-phosphorylatable GRAB mutant S169/180A promoted axonal outgrowth to a greater extent than did the phospho-mimic 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 was 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.SIGNIFICANCE STATEMENTWhile axon outgrowth requires membrane supply for surface expansion, the molecular mechanisms regulating the membrane transport in growing axons remains unclear. Here, we demonstrate that GRAB, a guanine nucleotide exchange factor for Rab8, is a novel regulator of axon outgrowth. GRAB promotes the axonal membrane transport by mediating the interaction between Rab11 and Rab8 in neurons. The activity of GRAB is regulated by phosphorylation with Cdk5. We describe an in vivo role for GRAB and its Cdk5 phosphorylation during neuronal migration and process formation in embryonic brains. Thus the membrane supply for axonal outgrowth is regulated by Cdk5 through the Rab11-GRAB-Rab8 cascade.