ADP Ribosylation Factor 6 Regulates Neuronal Migration in the Developing Cerebral Cortex through FIP3/Arfophilin-1-dependent Endosomal Trafficking of N-cadherin.
During neural development, endosomal trafficking controls cell shape and motility through the polarized transport of membrane proteins related to cell-cell and cell-extracellular matrix interactions. ADP ribosylation factor 6 (Arf6) is a critical small GTPase that regulates membrane trafficking between the plasma membrane and endosomes. We herein demonstrated that the knockdown of endogenous Arf6 in mouse cerebral cortices led to impaired neuronal migration in the intermediate zone and cytoplasmic retention of N-cadherin and syntaxin12 in migrating neurons. Rescue experiments with separation-of-function Arf6 mutants identified Rab11 family-interacting protein 3 (FIP3)/Arfophilin-1, a dual effector for Arf6 and Rab11, as a downstream effector of Arf6 in migrating neurons. The knockdown of FIP3 led to impaired neuronal migration in the intermediate zone and cytoplasmic retention of N-cadherin in migrating neurons, similar to that of Arf6, which could be rescued by the coexpression of wild-type FIP3 but not FIP3 mutants lacking the binding site for Arf6 or Rab11. These results suggest that Arf6 regulates cortical neuronal migration in the intermediate zone through the FIP3-dependent endosomal trafficking.
Department of Anatomy, Kitasato University School of Medicine , Sagamihara, Kanagawa 252-0374, Japan.
Yoshinobu
Y
Hara
Department of Anatomy, Kitasato University School of Medicine , Sagamihara, Kanagawa 252-0374, Japan.
Masahiro
M
Fukaya
Department of Anatomy, Keio University School of Medicine , Tokyo 160-8582, Japan.
Kanehiro
0000-0002-2757-363X
K
Hayashi
Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Takeshi
0000-0002-8650-4474
T
Kawauchi
Department of Anatomy, Keio University School of Medicine , Tokyo 160-8582, Japan.
Kazunori
0000-0003-1864-9425
K
Nakajima
Department of Anatomy, Kitasato University School of Medicine , Sagamihara, Kanagawa 252-0374, Japan.
Hiroyuki
H
Sakagami
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001693:Biological Transport, Active / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D050765:Qa-SNARE Proteins / Q000378:metabolism
D000089982:ADP-Ribosylation Factor 6; D015820:Cadherins; D002352:Carrier Proteins; C489083:Cdh2 protein, mouse; D050765:Qa-SNARE Proteins; C000593197:Rab11-FIP3 protein, mouse; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020727:ADP-Ribosylation Factors; C000715727:Arf6 protein, mouse
Arf6; N-cadherin; layer formation; membrane trafficking; migration; receptor recycling