Molecular specification of dopaminergic neuron diversity

PROJECT SUMMARY Dopamine is produced by a small but impactful subset of neurons in the eye and brain. Because this neuromodulator plays a critical role in a host of mental illnesses and diseases, it is vital to understand how dopamine neuron subsets are established and maintained. Our preliminary data show that the serine-threonine kinase LKB1 is required to restrict the number of dopaminergic neurons in the retina. In addition, we identify new dopaminergic cell subsets and show that LKB1 is cell-intrinsically required in inhibitory interneurons to modulate dopamine neuron diversity using molecular and neurogenetic approaches. This is a compelling result because factors that control the number and type of neurons that produce dopamine have remained elusive. To understand how LKB1 regulates dopamine neuron diversity, we have devised a strategy encompassing neural identity and connectivity mapping, cell-type specific intersectional genetic and viral strategies, molecular and biochemical studies, and functional analysis. We propose three aims. In Aim 1, we ask whether LKB1 is spatially and temporally sufficient to instruct dopamine neuron diversity by modulating this kinase in specific locations and at particular times. In Aim 2, we identify the mechanism through which LKB1 functions and test the hypothesis that LKB1-AMPK signaling plays a critical role. In Aim 3, we extend our analysis to the midbrain to test whether LKB1 is similarly required in this disease-relevant brain region to limit dopamine neuron diversity. Identifying a kinase pathway that precisely controls dopamine neuron diversity is surprising, so completing these aims will markedly advance our understanding of how dopaminergic neurons are endowed with their unique properties. In addition, these results will provide new therapeutic avenues for restoring dopamine production in the context of disease.