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Development. 2019 Feb 4;146(3). pii: dev172106. doi: 10.1242/dev.172106.

A crucial role for Arf6 in the response of commissural axons to Slit.

Author information

1
Developmental Neurobiology Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan.
2
Department of Neurology, Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
3
Department of Neurology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
4
Department of Physiological Chemistry, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
5
Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
6
State Key Laboratory of Biomembrane and Membrane Biology, Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University School of Life Sciences, Beijing 100871, China.
7
Developmental Neurobiology Unit, Okinawa Institute of Science and Technology Graduate University, Onna, Okinawa 904-0495, Japan jkawada@cclm.med.kyushu-u.ac.jp jane-wu@northwestern.edu.
8
Center for Advanced Medical Innovation, Kyushu University, Fukuoka 812-8582, Japan.
9
Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
10
Department of Neurology, Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA jkawada@cclm.med.kyushu-u.ac.jp jane-wu@northwestern.edu.

Abstract

A switch in the response of commissural axons to the repellent Slit is crucial for ensuring that they cross the ventral midline only once. However, the underlying mechanisms remain to be elucidated. We have found that both endocytosis and recycling of Robo1 receptor are crucial for modulating Slit sensitivity in vertebrate commissural axons. Robo1 endocytosis and its recycling back to the cell surface maintained the stability of axonal Robo1 during Slit stimulation. We identified Arf6 guanosine triphosphatase and its activators, cytohesins, as previously unknown components in Slit-Robo1 signalling in vertebrate commissural neurons. Slit-Robo1 signalling activated Arf6. The Arf6-deficient mice exhibited marked defects in commissural axon midline crossing. Our data showed that a Robo1 endocytosis-triggered and Arf6-mediated positive-feedback strengthens the Slit response in commissural axons upon their midline crossing. Furthermore, the cytohesin-Arf6 pathways modulated this self-enhancement of the Slit response before and after midline crossing, resulting in a switch that reinforced robust regulation of axon midline crossing. Our study provides insights into endocytic trafficking-mediated mechanisms for spatiotemporally controlled axonal responses and uncovers new players in the midline switch in Slit responsiveness of commissural axons.

KEYWORDS:

Arf6; Axon guidance; Commissural neurons; Endocytic recycling; Midline; Slit-Robo

PMID:
30674481
PMCID:
PMC6382006
[Available on 2020-02-01]
DOI:
10.1242/dev.172106

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