Correct setup of the substantia nigra requires Reelin-mediated fast, laterally-directed migration of dopaminergic neurons.

Ankita Ravi Vaswani,Hans-Ulrich Fried,Sandra Blaess,Oliver Brüstle,Beatrice Weykopf,Cathleen Hagemann

doi:10.7554/elife.41623

Ankita Ravi Vaswani, Hans-Ulrich Fried + Show 4 more

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https://doi.org/10.7554/elife.41623

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Abstract

Midbrain dopaminergic (mDA) neurons migrate to form the laterally-located substantia nigra pars compacta (SN) and medially-located ventral tegmental area (VTA), but little is known about the underlying cellular and molecular processes. Here we visualize the dynamic cell morphologies of tangentially migrating SN-mDA neurons in 3D and identify two distinct migration modes. Slow migration is the default mode in SN-mDA neurons, while fast, laterally-directed migration occurs infrequently and is strongly associated with bipolar cell morphology. Tangential migration of SN-mDA neurons is altered in absence of Reelin signaling, but it is unclear whether Reelin acts directly on migrating SN-mDA neurons and how it affects their cell morphology and migratory behavior. By specifically inactivating Reelin signaling in mDA neurons we demonstrate its direct role in SN-mDA tangential migration. Reelin promotes laterally-biased movements in mDA neurons during their slow migration mode, stabilizes leading process morphology and increases the probability of fast, laterally-directed migration.

Highlights

Dopaminergic neurons in the ventral midbrain are the major source of dopamine in the mammalian brain
Dysfunction in the dopaminergic system is associated with schizophrenia, addiction and depression, and degeneration of Midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SN) results in the motor symptoms of Parkinson’s disease (Grace and Bunney, 1980; Volkow and Morales, 2015; Przedborski, 2017). mDA neurons originate in the floor plate of the ventral mesencephalon, from where they migrate to cluster into the laterally-positioned SN, the medially-located ventral tegmental area (VTA) and the posterior retrorubral field
We demonstrate that migrating mDA neurons undergo dynamic changes in cell morphology and show that fast, directed migratory spurts are strongly associated with bipolar morphology

Summary

Introduction

Dopaminergic neurons in the ventral midbrain (mDA neurons) are the major source of dopamine in the mammalian brain. SN-mDA neurons project predominantly to the dorsal striatum and modulate voluntary movement (Weisenhorn et al, 2016), while VTA-mDA neurons project to various forebrain targets, including the prefrontal cortex, nucleus accumbens and basolateral amygdala, and are important for the regulation of cognitive function and reward behavior (Morales and Margolis, 2017). How this anatomy is setup during development remains unclear. We have previously shown that both SN- and VTA-mDA neurons

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