Temporal-spatial changes in Sonic Hedgehog expression and signaling reveal different potentials of ventral mesencephalic progenitors to populate distinct ventral midbrain nuclei
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BACKGROUND: The ventral midbrain contains a diverse array of neurons, including dopaminergic neurons of the ventral tegmental area (VTA) and substantia nigra (SN) and neurons of the red nucleus (RN). Dopaminergic and RN neurons have been shown to arise from ventral mesencephalic precursors that express Sonic Hedgehog (Shh). However, Shh expression, which is initially confined to the mesencephalic ventral midline, expands laterally and is then downregulated in the ventral midline. In contrast, expression of the Hedgehog target gene Gli1 initiates in the ventral midline prior to Shh expression, but after the onset of Shh expression it is expressed in precursors lateral to Shh-positive cells. Given these dynamic gene expression patterns, Shh and Gli1 expression could delineate different progenitor populations at distinct embryonic time points. RESULTS: We employed genetic inducible fate mapping (GIFM) to investigate whether precursors that express Shh (Shh-GIFM) or transduce Shh signaling (Gli1-GIFM) at different time points give rise to different ventral midbrain cell types. We find that precursors restricted to the ventral midline are labeled at embryonic day (E)7.5 with Gli1-GIFM, and with Shh-GIFM at E8.5. These precursors give rise to all subtypes of midbrain dopaminergic neurons and the anterior RN. A broader domain of progenitors that includes the ventral midline is marked with Gli1-GIFM at E8.5 and with Shh-GIFM at E9.5; these fate-mapped cells also contribute to all midbrain dopaminergic subtypes and to the entire RN. In contrast, a lateral progenitor domain that is labeled with Gli1-GIFM at E9.5 and with Shh-GIFM at E11.5 has a markedly reduced potential to give rise to the RN and to SN dopaminergic neurons, and preferentially gives rise to the ventral-medial VTA. In addition, cells derived from Shh- and Gli1-expressing progenitors located outside of the ventral midline give rise to astrocytes. CONCLUSIONS: We define a ventral midbrain precursor map based on the timing of Gli1 and Shh expression, and suggest that the diversity of midbrain dopaminergic neurons is at least partially determined during their precursor stage when their medial-lateral position, differential gene expression and the time when they leave the ventricular zone influence their fate decisions.
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Midbrain dopamine neurons originate from the mesodiencephalic floorplate, a region at the ventral midline defined by Shh+ and Foxa2+ expression.
“These neurons originate from the mesodiencephalic floorplate (FP), a region at the ventral midline defined by the mRNA expression of Shh+ and Foxa2+ [67–73].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [70]
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- Authors
- Blaess, S., Bodea, G. O., Kabanova, A., Chanet, S., Mugniery, E., Derouiche, A., Stephen, D., & Joyner, A. L.
- Affiliations
- University of Bonn (DE)
- Centre National de la Recherche Scientifique (FR)
- Goethe University Frankfurt (DE)
- Corresponding author
- Blaess, Sandra
- Bodea, Gabriela O
- Kabanova, Anna
- Chanet, Soline
- Derouiche, Amin
- Stephen, Daniel
- Joyner, Alexandra L
- Venue
- Neural Development
- Published
- 2011-06-20
- Volume
- 6
- Issue
- 1
- Pages
- 29-29
- ISSN
- 1749-8104 (ISSN-L)
- PMC
- PMC3135491
- OpenAlex
- W1990251289
- Cited by
- 133
- References
- 43
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 11 · 2023: 8 · 2022: 11 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 4 · 2017: 9 · 2016: 5 · 2015: 14 · 2014: 8 · 2013: 12 · 2012: 12
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Neural Development (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (TP C1, SFB TR 3)
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Sonic hedgehog signaling, Gli1, ventral midbrain, dopaminergic neurons, ventral tegmental area, substantia nigra, red nucleus, astrocytes, midbrain development, cell fate specification, Hedgehog signaling, ventral midline
- MeSH terms
- Zinc Finger Protein GLI1, Animals, Astrocytes, Brain Mapping, Cell Differentiation, Dopamine, Female, Fluorescent Antibody Technique, Mesencephalon, Neurons, Oculomotor Nerve, Pregnancy, Red Nucleus, RNA, Substantia Nigra, Signal Transduction, In Situ Hybridization, Mice, Kruppel-Like Transcription Factors, Hedgehog Proteins, Neural Stem Cells
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