Grant: Operating Grant

Degeneration of midbrain dopaminergic neurons (mDA) is the principal cause of one the most prominent human neurological disorder, Parkinson's disease. Graft of dopaminergic neurons newly generated from stem cells represent a promising therapeutic avenue. A major factor limiting success in transplantation studies is the inappropriate re-innervation of the grafted neurons; thereby underscoring the importance of identifying factors regulating axon projection and connectivity of mDA neurons. During the last decade, numerous proteins have been shown to have a role to guide developing axons in the brain. Though considerable progress has been made to identify these molecules, their receptors and their intracellular signaling pathway, very little is known about their localization and function in the dopaminergic system. We recently discovered that transcription factors Lmx1a and Lmx1b regulate dopaminergic axon targeting. Double mutant mice for these transcription factors have drastic dopaminergic axon guidance defects. Our gene expression profiling experiments comparing these mutants to control animals have generated an exceptional list of genes regulated by these transcription factors. In this application, we propose to investigate the role of Lmx1a/b and downstream target genes in dopamine neuron circuit formation and maintenance. We will use mutant mice and novel in vivo and in vitro techniques to observe and control axon behavior in response to guidance cues. Our research project will shed a new light on mechanisms involved in the formation and maintenance of dopaminergic axonal network. In the long term, our findings will likely contribute to improvement of cell replacement therapies for Parkinson's disease.