Developmental Underpinnings of Dopamine Neuron Diversity

Pereira Luppi, Maria Milagros

doi:https://doi.org/10.21985/n2-vhv9-6y64

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Developmental Underpinnings of Dopamine Neuron Diversity

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Dopamine (DA) neurons are involved in many brain functions, and their dysfunction is associated with several neurodegenerative diseases. In recent years, our lab and others have found that DA neurons are molecularly diverse through single-cell gene expression profiling. An outstanding question in the field is whether this heterogeneity is encoded early in development. All midbrain DA neurons originate from the embryonic floor plate, which can be subdivided into a medial Sox6+ and a lateral Sox6-/Otx2+ progenitor domain. Current models disagree on the molecular identity of the medial vs. lateral progenitor domain descendants, with some studies suggesting that medially located progenitors give rise to substantia nigra pars compacta (SNc) neurons, one of the main DA neuron clusters, and others suggesting that the lateral progenitor domain is also a prominent source of SNc neurons. Besides being expressed in DA progenitors, transcription factor Sox6 is also a primary classifier of DA neurons, defining Sox6+ and Sox6- cohorts, particularly in the SNc. Sox6+ neurons include an Aldh1a1+ population, vulnerable in Parkinson’s Disease models, while other DA neurons are resilient. To investigate whether there is a relationship between progenitor heterogeneity and the diversity we observe in the adult midbrain, we developed a set of lineage tracing tools to capture the entire history of Sox6 expression from the progenitor stage. We reveal distinct developmental histories between key dopamine neuronal cohorts, derived mainly from different progenitor pools, demonstrating a dual embryonic origin of the SNc. Moreover, our data suggest that Sox6+ progenitors have a higher propensity to generate vulnerable Aldh1a1+ neurons than resilient Calb1+ neurons. This implies that the embryonic progenitor domain, subdivided by Sox6, is already biased towards distinct DA neuron fates that could account for their later vulnerability. Leveraging the power of intersectional/subtractive genetic methods and Sox6 as an anchor, we provide a developmental perspective into how diversity is generated in the early embryo.

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