Netrin-1 and slit-2 regulate and direct neurite growth of ventral midbrain dopaminergic neurons.
We investigated the roles of netrin-1 and slit-2 in regulation and navigation of dopamine (DA) axon growth using an explant culture preparation of embryonic ventral midbrain (embryonic day 14) and a co-culture system. We found that netrin-1 protein significantly enhanced DA axonal outgrowth and promoted DA axonal outgrowth in a co-culture system of netrin-1 expressing cells. Such effects were mediated by the receptor DCC as demonstrated by antibody perturbation of the DCC receptor. In contrast, slit-2 inhibited DA neuron extensions and repelled DA neurite growth. These slit-2 activities required robo receptors since the reduced neurite extension was abolished by addition of excess robo receptors. In this system, netrin-1 stimulated and slit-2 opposed DA neurite growth. Such regulation may be important for DA axonal maintenance, regeneration, and phenotypic target recognition.
Lin
Ling
L
Neuroregeneration Laboratories, Mailman Research Center, Harvard Medical School/McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. llin@mclean.harvard.edu
Rao
Yi
Y
Isacson
Ole
O
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D000075389:DCC Receptor; D004298:Dopamine / Q000378:metabolism*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D020439:Growth Cones / Q000378:metabolism; D006131:Growth Inhibitors / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000494:pharmacology; D000075388:Netrin-1; D016501:Neurites / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism* / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000098552:Slit Homolog 2 Protein; D000097905:Roundabout Proteins
D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; D004298:Dopamine; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006131:Growth Inhibitors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075388:Netrin-1; D024661:Potassium Channels, Inwardly Rectifying; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; D014446:Tyrosine 3-Monooxygenase; D000098552:Slit Homolog 2 Protein; C501909:DCC protein, human; C000617351:NTN1 protein, human; C000617354:Ntn1 protein, rat; C498890:ROBO2 protein, human; D000097905:Roundabout Proteins