Netrin induces down-regulation of its receptor, Deleted in Colorectal Cancer, through the ubiquitin-proteasome pathway in the embryonic cortical neuron.
The proper regulation of temporal and spatial expression of the axon guidance cues and their receptors is critical for the normal wiring of nervous system during development. Netrins, a family of secreted guidance cues, are involved in the midline crossing of spinal commissural axons and in the guidance of cortical efferents. Axons normally lose the responsiveness to their attractants when they arrive at their targets, where the attractant is produced. However the molecular mechanism is still unknown. We investigated the molecular mechanism of down-regulation of netrin-1 signaling in the embryonic cortical neurons. Netrin-1 induced the ubiquitination and proteolytic cleavage of Deleted in Colorectal Cancer (DCC), a transmembrane receptor for netrin, in dissociated cortical neurons. A dramatic decrease of DCC level particularly on the cell surface was also observed after netrin-1 stimulation. Specific ubiquitin-proteasome inhibitors prevented the netrin-induced DCC cleavage and decrease of cell surface DCC. We suggest that the ligand-mediated down-regulation of DCC might participate in the loss of netrin-responsiveness in the developing nervous system.
Kim
Tae-Hong
TH
Department of Pediatrics, Institute of Medical Science, College of Medicine, Dong-A University, Busan, South Korea.
Lee
Hyun Kyoung
HK
Seo
In Ae
IA
Bae
Hae Rahn
HR
Suh
Duk Joon
DJ
Wu
Jane
J
Rao
Yi
Y
Hwang
Kyu-Geun
KG
Park
Hwan Tae
HT
D000818:Animals; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology*; D000075389:DCC Receptor; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D006801:Humans; D009414:Nerve Growth Factors / Q000494:pharmacology*; D000075388:Netrin-1; D009474:Neurons / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501909:DCC protein, human; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617354:Ntn1 protein, rat; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D000075388:Netrin-1; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex