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Genetic control of midbrain dopaminergic neuron development

Advanced Review

Sandra Blaess, Siew‐Lan Ang

Published Online: Jan 06 2015

DOI: 10.1002/wdev.169

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Abstract Midbrain dopaminergic neurons are involved in regulating motor control, reward behavior, and cognition. Degeneration or dysfunction of midbrain dopaminergic neurons is implicated in several neuropsychiatric disorders such as Parkinson's disease, substance use disorders, depression, and schizophrenia. Understanding the developmental processes that generate midbrain dopaminergic neurons will facilitate the generation of dopaminergic neurons from stem cells for cell replacement therapies to substitute degenerating cells in Parkinson's disease patients and will forward our understanding on how functional diversity of dopaminergic neurons in the adult brain is established. Midbrain dopaminergic neurons develop in a multistep process. Following the induction of the ventral midbrain, a distinct dopaminergic progenitor domain is specified and dopaminergic progenitors undergo proliferation, neurogenesis, and differentiation. Subsequently, midbrain dopaminergic neurons acquire a mature dopaminergic phenotype, migrate to their final position and establish projections and connections to their forebrain targets. This review will discuss insights gained on the signaling network of secreted molecules, cell surface receptors, and transcription factors that regulate specification and differentiation of midbrain dopaminergic progenitors and neurons, from the induction of the ventral midbrain to the migration of dopaminergic neurons. WIREs Dev Biol 2015, 4:113–134. doi: 10.1002/wdev.169 This article is categorized under: Nervous System Development > Vertebrates: General Principles Nervous System Development > Vertebrates: Regional Development

Dopaminergic system in the human and mouse brain. Schematics of the human and mouse brain. PFC, prefrontal cortex; RRF, retrorubral fiels; SNpc, substantia nigra pars compacta; VTA, ventral tegmental area.

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Migration of mDA neurons. Schematic of coronal section through E12.5 ventral midbrain. See main text for details.

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Genetic network regulating the differentiation process of mDA neurons. The network is based on loss‐ or gain‐of‐function experiments in mice, unless indicated otherwise. Arrows indicate activation; red lines indicate inhibition. Solid lines: based on loss‐of‐function data (plus gain‐of‐function for some interactions). Dotted lines: only based on gain of function data. Solid lines: potential direct interaction, based on CHIP‐Seq data. Dark green boxes: expressed in differentiated mDA neurons, light green boxes with dark green frame: expressed in mDA progenitors and mDA neurons. Interlinked ovals: formation of a protein complex. Sfpq: transcriptional co‐repressor. Asterisks: experiments in cell culture.

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Genetic network regulating the specification of dopaminergic identity and neuronal commitment in mDA progenitors. The network is based on loss‐ or gain‐of‐function experiments in mice, unless indicated otherwise. Arrows indicate activation; red lines indicate inhibition. Solid lines: based on loss‐of‐function data (plus gain‐of‐function for some interactions). Dotted lines: only based on gain‐of‐function data. Dashed line: interaction observed in gain‐of‐function, but not in loss‐of‐function experiments. Thick line: potential direct interaction, based on CHIP‐Seq data. Green boxes: expressed in mDA progenitors. §: in loss‐of function experiments only inactivation of both Lmx1a and Lmx1b lead to complete loss of Corin, Msx1, Neurog2, and Ascl1 expression. Asterisks: experiments in cell culture.

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Expression patterns of a key set of secreted molecules and transcription factors regulating specification of mDA identity in mDA progenitors. Schematics depicting expression domains in the developing brain in sagittal and coronal views. The expression of transcription factors is only depicted in coronal sections, since the transcription factors shown are expressed along the entire anterior–posterior extent of the mDA progenitor domain and of the field of differentiated mDA neurons. The exception is the expression of En1/2, which is excluded from the most rostral progenitor domain. The expression domains of Wnt1, Shh, Fgf8, Gli1, and Foxa1/2 are colored in, the expression domains of Msx1, Lmx1a, Lmx1b, Otx2, En1/2, and Pax2/5 are outlined. FP, floorplate; IS, isthmus; ML, mantle layer; NC, notochord; VZ, ventricular zone.

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Development of mDA neurons. Key factors expressed at different stages of mDA neuron development. Factors expressed in all mDA progenitors and/or neurons are depicted in black. Factors expressed in subsets of mDA progenitors and/or neurons are depicted in white. Factors expressed specifically in mDA progenitors and/or neurons in the ventral midbrain are in bold. See main text and Figure for further details. ML, mantle layer; VZ, ventricular zone.

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