The Matricellular Protein R-Spondin 2 Promotes Midbrain Dopaminergic Neurogenesis and Differentiation
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The development of midbrain dopaminergic (mDA) neurons is controlled by multiple morphogens and transcription factors. However, little is known about the role of extracellular matrix proteins in this process. Here we examined the function of roof plate-specific spondins (RSPO1-4) and the floor plate-specific, spondin 1 (SPON1). Only RSPO2 and SPON1 were expressed at high levels during mDA neurogenesis, and the receptor LGR5 was expressed by midbrain floor plate progenitors. Surprisingly, RSPO2, but not SPON1, specifically promoted the differentiation of mDA neuroblasts into mDA neurons in mouse primary cultures and embryonic stem cells (ESCs). In addition, RSPO2 was found to promote not only mDA differentiation, but also mDA neurogenesis in human ESCs. Our results thus uncover an unexpected function of the matricellular protein RSPO2 and suggest an application to improve mDA neurogenesis and differentiation in human stem cell preparations destined to cell replacement therapy or drug discovery for Parkinson disease.
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R-Spondin 2 has been implied in the development of midbrain dopaminergic neurons and has been linked to fear extinction processes in the amygdala.
“R-Spondin 2 has been implied in the development of midbrain dopaminergic neurons (Gyllborg et al., 2018) and has been linked to fear extinction processes in the amygdala (McCullough et al., 2016).”
From Epigenome-wide DNA methylation in unipolar depression: predictive biomarker of antidepressant treatment response? (2024) · cites this paper as Gyllborg et al., 2018
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Development, wiring and function of dopamine neuron subtypes
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- Authors
- Gyllborg, D., Ahmed, M., Toledo, E. M., Theofilopoulos, S., Yang, S., ffrench-Constant, C., & Arenas, E.
- Affiliations
- Karolinska Institutet (SE)
- MRC Centre for Regenerative Medicine (GB)
- Corresponding author
- Arenas, Ernest
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 11
- Issue
- 3
- Pages
- 651-664
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC6135723
- OpenAlex
- W2888243582
- Cited by
- 28
- References
- 60
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 2 · 2020: 3 · 2019: 3
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Swedish Research Council (2011-3116, 2011-3318, 2016-01526)
- Swedish Foundation for Strategic Research (SB16-0065)
- European Commission
- Karolinska Institutet
- Hjärnfonden (FO2015:0202, FO2017:0059)
- Cancerfonden (2016/572)
- SFO Strat Regen (SG-2018)
- NeuroStemCellRepair
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- RSPO2, matricellular proteins, midbrain dopaminergic neurons, dopaminergic neurogenesis, dopaminergic differentiation, extracellular matrix, SPON1, embryonic stem cells, Parkinson's disease, cell replacement therapy
- MeSH terms
- Human Embryonic Stem Cells, R-Spondins, Animals, Cells, Cultured, Female, Humans, Mesencephalon, Thrombospondins, Intercellular Signaling Peptides and Proteins, Mice, Neurogenesis, Dopaminergic Neurons
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