A central role for RhoA during oligodendroglial maturation in the switch from netrin-1-mediated chemorepulsion to process elaboration.
The guidance cue netrin-1 and its receptor Deleted in Colorectal Cancer play distinct roles during different stages of oligodendrocyte development. A gradient of netrin-1 repels migrating oligodendrocyte precursor cells (OPCs) in the embryonic spinal cord by promoting process collapse, but later in development netrin-1 increases oligodendrocyte process extension and branching. Here we investigate the intracellular mechanism that governs this switch in response to netrin-1, and focus on the role of the GTPase RhoA and its effector Rho Kinase (ROCK) downstream of netrin-1 in OPCs and maturing oligodendrocytes. In OPCs, we show that netrin-1 induces a sustained increase in RhoA activity that requires Deleted in Colorectal Cancer function. Furthermore, we demonstrate that activation of RhoA and ROCK is required for the reduction in OPC process length triggered by netrin-1, and for the chemorepellent response made by OPCs to netrin-1. Unlike OPCs, application of netrin-1 to oligodendrocytes decreases RhoA activity. We demonstrate that inactivation of RhoA is essential for netrin-1 to increase oligodendrocyte process branching. We conclude that netrin-1 induces distinct morphological responses in OPCs and oligodendrocytes through differential regulation of RhoA activity.
Rajasekharan
Sathyanath
S
Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4.
Bin
Jenea M
JM
Antel
Jack P
JP
Kennedy
Timothy E
TE
D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D000075388:Netrin-1; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000502:physiology*; D000097573:Red Fluorescent Protein; D000070584:Tripartite Motif Proteins
D000577:Amides; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D009414:Nerve Growth Factors; D000075388:Netrin-1; D009687:Nuclear Proteins; D011725:Pyridines; D025521:Tumor Suppressor Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000097573:Red Fluorescent Protein; C000617354:Ntn1 protein, rat; C489295:Trim27 protein, rat; D000070584:Tripartite Motif Proteins; C108830:Y 27632