Midbrain dopaminergic axons are guided longitudinally by Slit/Robo signaling

• Main Author: Dugan, James P
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2008
• Subjects: Cellular biology; Molecular biology; Neurology; Neurosciences
• ISBN: 9780549701071; 0549701079

Dopaminergic neurons from the ventral mesencephalon/diencephalon (mesodiencephalon) form vital pathways constituting the majority of the brain's dopamine systems. Mesodiencephalic dopaminergic (mdDA) neurons extend longitudinal projections anteriorly, ascending toward forebrain targets. How mdDA neurons extend axons through their native environment to connect with their targets is not well understood. Recently the Slits, and their associated receptors of the Robo family, have been identified as a means of descending longitudinal axon guidance. mdDA axons grow out of and parallel to Slit-positive regions within the midbrain and forebrain and express Robo receptors. To test the role of Slit/Robo signaling on mdDA neurons, we examined their projections in Slit and Robo knockout mice. Using in vivo and in vitro assays with a tyrosine hydroxylase antibody, we were able to show significant pathfinding errors in mdDA axons in Slit1/2 and Robo1/2 knockout mice when compared to heterozygous controls. Mutant mdDA axons spread out in the diencephalon to form a wider tract. Phenotypes included invasion of the ventral midline, consistent with Slit repulsion. However, individual axons also wandered in aberrant dorsal trajectories. We suggest that Slit/Robo signaling is necessary for correct dorsoventral positioning and precise pathfinding of dopaminergic longitudinal axons, as well as serving a repellant function. Degeneration of mdDA pathways has been implicated in Parkinson's disease and schizophrenia. These results may provide insights into the cellular characteristics necessary for treatment of neurological disorders associated with mdDA neuronal degeneration.