Dataset Information

Netrin-DCC, Robo-Slit, and heparan sulfate proteoglycans coordinate lateral positioning of longitudinal dopaminergic diencephalospinal axons.

ABSTRACT: 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.

SUBMITTER: Kastenhuber E

PROVIDER: S-EPMC4404407 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Netrin-DCC, Robo-Slit, and heparan sulfate proteoglycans coordinate lateral positioning of longitudinal dopaminergic diencephalospinal axons.

Kastenhuber Edda E Kern Ursula U Bonkowsky Joshua L JL Chien Chi-Bin CB Driever Wolfgang W Schweitzer Joern J

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090701 28

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 ...[more]

PMID: 19605629

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Project description:BackgroundSLIT-ROBO families of proteins mediate axon pathfinding and their expression is not solely confined to nervous system. Aberrant expression of SLIT-ROBO genes was repeatedly shown in a wide variety of cancers, yet data about their collective behavior in hepatocellular carcinoma (HCC) is missing. Hence, we quantified SLIT-ROBO transcripts in HCC cell lines, and in normal and tumor tissues from liver.MethodsExpression of SLIT-ROBO family members was quantified by real-time qRT-PCR in 14 HCC cell lines, 8 normal and 35 tumor tissues from the liver. ANOVA and Pearson's correlation analyses were performed in R environment, and different clinicopathological subgroups were pairwise compared in Minitab. Gene expression matrices of cell lines and tissues were analyzed by Mantel's association test.ResultsGenewise hierarchical clustering revealed two subgroups with coordinate expression pattern in both the HCC cell lines and tissues: ROBO1, ROBO2, SLIT1 in one cluster, and ROBO4, SLIT2, SLIT3 in the other, respectively. Moreover, SLIT-ROBO expression predicted AFP-dependent subgrouping of HCC cell lines, but not that of liver tissues. ROBO1 and ROBO2 were significantly up-regulated, whereas SLIT3 was significantly down-regulated in cell lines with high-AFP background. When compared to normal liver tissue, ROBO1 was found to be significantly overexpressed, while ROBO4 was down-regulated in HCC. We also observed that ROBO1 and SLIT2 differentiated histopathological subgroups of liver tissues depending on both tumor staging and differentiation status. However, ROBO4 could discriminate poorly differentiated HCC from other subgroups.ConclusionThe present study is the first in comprehensive and quantitative evaluation of SLIT-ROBO family gene expression in HCC, and suggests that the expression of SLIT-ROBO genes is regulated in hepatocarcinogenesis. Our results implicate that SLIT-ROBO transcription profile is bi-modular in nature, and that each module shows intrinsic variability. We also provide quantitative evidence for potential use of ROBO1, ROBO4 and SLIT2 for prediction of tumor stage and differentiation status.

Dataset Information

Netrin-DCC, Robo-Slit, and heparan sulfate proteoglycans coordinate lateral positioning of longitudinal dopaminergic diencephalospinal axons.

Publications

Netrin-DCC, Robo-Slit, and heparan sulfate proteoglycans coordinate lateral positioning of longitudinal dopaminergic diencephalospinal axons.

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