期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 78, 期 6, 页码 2797-2820出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-020-03663-z
关键词
UNC5; Netrin-1; Cerebellar EGL neurons; Axonal repulsion; Lipid raft microdomain; Single particle tracking
资金
- Spanish MINECO [SAF2016-76340R]
- CIBERNED, Spanish MECD [FPU14/02156, BES2014-067857]
- TERCEL [RD12/0019/0011]
- ERDF funds
- Juan de la Cierva postdoctoral fellowship
- MECD [FPU14/02156, BES-2014-067857]
- NHMRC [1147600]
- Australian Government through an ARC LIEF Grant [LE130100078]
- National Health and Medical Research Council of Australia [1147600] Funding Source: NHMRC
The study found that the distribution of UNC5 receptors in cholesterol-enriched raft microdomains is heterogeneous and has functional consequences for axonal chemorepulsion against Netrin-1.
During brain development, Uncoordinated locomotion 5 (UNC5) receptors control axonal extension through their sensing of the guidance molecule Netrin-1. The correct positioning of receptors into cholesterol-enriched membrane raft microdomains is crucial for the efficient transduction of the recognized signals. However, whether such microdomains are required for the appropriate axonal guidance mediated by UNC5 receptors remains unknown. Here, we combine the use of confocal microscopy, live-cell FRAP analysis and single-particle tracking PALM to characterize the distribution of UNC5 receptors into raft microdomains, revealing differences in their membrane mobility properties. Using pharmacological and genetic approaches in primary neuronal cultures and brain cerebellar explants we further demonstrate that disrupting raft microdomains inhibits the chemorepulsive response of growth cones and axons against Netrin-1. Together, our findings indicate that the distribution of all UNC5 receptors into cholesterol-enriched raft microdomains is heterogeneous and that the specific localization has functional consequences for the axonal chemorepulsion against Netrin-1.
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