Netrin-DCC, Robo-Slit, and heparan sulfate proteoglycans coordinate lateral positioning of longitudinal dopaminergic diencephalospinal axons
- Kastenhuber, E., Kern U., Bonkowsky, J.L., Chien, C.B., Driever, W., and Schweitzer, J.
- The Journal of neuroscience : the official journal of the Society for Neuroscience 29(28): 8914-8926 (Journal)
- Registered Authors
- Bonkowsky, Joshua, Chien, Chi-Bin, Driever, Wolfgang, Kastenhuber, Edda, Schweitzer, Jörn
- MeSH Terms
- Animals, Genetically Modified
- Gene Expression Regulation, Developmental
- Green Fluorescent Proteins/genetics
- Heparan Sulfate Proteoglycans/metabolism*
- Nerve Growth Factors/genetics
- Nerve Growth Factors/metabolism
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Signal Transduction/genetics
- Signal Transduction/physiology*
- Spinal Cord/physiology*
- Tumor Suppressor Proteins/genetics
- Tumor Suppressor Proteins/metabolism
- Tyrosine 3-Monooxygenase/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- 19605629 Full text @ J. Neurosci.
Kastenhuber, E., Kern U., Bonkowsky, J.L., Chien, C.B., Driever, W., and Schweitzer, J. (2009) Netrin-DCC, Robo-Slit, and heparan sulfate proteoglycans coordinate lateral positioning of longitudinal dopaminergic diencephalospinal axons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 29(28):8914-8926.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes