Abstract
The floor plate, an essential ventral midline organizing center that produces the morphogen Shh, has distinct properties along the neuraxis. The neurogenic potential of the floor plate and its underlying mechanisms remain unknown. Using Shh as a driver for lineage analysis, we found that the mouse midbrain, but not the hindbrain, floor plate is neurogenic, giving rise to dopamine (DA) neurons. Distinct spatiotemporal Shh and Wnt expression may distinguish the neurogenetic potential of these structures. We discovered an inhibitory role for Shh: removal of Shh resulted in neurogenesis from the hindbrain midline and, conversely, high doses of Shh inhibited proliferation and DA neuron production in midbrain cultures. We found that Wnt/beta-catenin signaling is necessary and sufficient for antagonizing Shh, DA progenitor marker induction and promotion of dopaminergic neurogenesis. These findings demonstrate how the dynamic interplay of canonical Wnt/beta-catenin signaling and Shh may orchestrate floor plate neurogenesis or a lack thereof.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cells, Cultured
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Female
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Gene Expression Regulation, Developmental
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Hepatocyte Nuclear Factor 3-beta / metabolism
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Homeodomain Proteins / metabolism
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LIM-Homeodomain Proteins
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Male
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Mesencephalon / cytology
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Mesencephalon / embryology
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Mesencephalon / physiology*
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurogenesis / physiology*
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Neurons / cytology
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Neurons / physiology*
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Otx Transcription Factors / metabolism
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Pregnancy
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Rhombencephalon / cytology
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Rhombencephalon / embryology
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Rhombencephalon / physiology
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Signal Transduction / physiology
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Stem Cell Niche / cytology
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Stem Cell Niche / physiology*
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Stem Cells / cytology
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Stem Cells / physiology
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Transcription Factors / metabolism
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Wnt Proteins / metabolism*
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beta Catenin / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Foxa2 protein, mouse
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Hedgehog Proteins
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Homeodomain Proteins
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LIM homeobox transcription factor 1 beta
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LIM-Homeodomain Proteins
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Lmx1a protein, mouse
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Nerve Tissue Proteins
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Neurog2 protein, mouse
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Otx Transcription Factors
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Otx2 protein, mouse
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Shh protein, mouse
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Transcription Factors
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Wnt Proteins
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beta Catenin
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Hepatocyte Nuclear Factor 3-beta