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The Journal of Neuroscience, July 15, 2009, 29(28):8914-8926; doi:10.1523/JNEUROSCI.0568-09.2009

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Development/Plasticity/Repair
Netrin-DCC, Robo-Slit, and Heparan Sulfate Proteoglycans Coordinate Lateral Positioning of Longitudinal Dopaminergic Diencephalospinal Axons

Edda Kastenhuber,¹ Ursula Kern,¹ Joshua L. Bonkowsky,^3,4 Chi-Bin Chien,³ Wolfgang Driever,^1,2 and Joern Schweitzer¹

¹Developmental Biology, Institute of Biology 1, Faculty of Biology and ²Freiburg Institute for Advanced Studies, University of Freiburg, 79104-D Freiburg, Germany, ³Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84132, and ⁴Department of Pediatric Neurology and Pediatrics, University of Utah Medical Center, Salt Lake City, Utah 84132

Correspondence should be addressed to either Dr. Joern Schweitzer or Dr. Wolfgang Driever, Institute of Biology 1, University of Freiburg, Hauptstrasse 1, D-79104 Freiburg, Germany, Email: joern.schweitzer{at}biologie.uni-freiburg.de or Email: driever{at}biologie.uni-freiburg.de

Longitudinal axons provide connectivity between remote areas of the nervous system. Although the molecular determinants driving commissural pathway formation have been well characterized, mechanisms specifying the formation of longitudinal axon tracts in the vertebrate nervous system are largely unknown. Here, we study axon guidance mechanisms of the longitudinal dopaminergic (DA) diencephalospinal tract. This tract is established by DA neurons located in the ventral diencephalon and is thought to be involved in modulating locomotor activity. Using mutant analysis as well as gain of function and loss of function experiments, we demonstrate that longitudinal DA axons navigate by integrating long-range signaling of midline-derived cues. Repulsive Robo2/Slit signaling keeps longitudinal DA axons away from the midline. In the absence of repulsive Robo2/Slit function, DA axons are attracted toward the midline by DCC (deleted in colorectal cancer)/Netrin1 signaling. Thus, Slit-based repulsion counteracts Netrin-mediated attraction to specify lateral positions of the DA diencephalospinal tract. We further identified heparan sulfate proteglycans as essential modulators of DA diencephalospinal guidance mechanisms. Our findings provide insight into the complexity of positioning far-projecting longitudinal axons and allow us to provide a model for DA diencephalospinal pathfinding. Simultaneous integrations of repulsive and attractive long-range cues from the midline act in a concerted manner to define lateral positions of DA longitudinal axon tracts.

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Received Feb. 3, 2009; accepted May 14, 2009.

Correspondence should be addressed to either Dr. Joern Schweitzer or Dr. Wolfgang Driever, Institute of Biology 1, University of Freiburg, Hauptstrasse 1, D-79104 Freiburg, Germany, Email: joern.schweitzer{at}biologie.uni-freiburg.de or Email: driever{at}biologie.uni-freiburg.de

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