Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle
Introduction: Alteration in the development, maturation, and projection of dopaminergic neurons has been proposed to be associated with several neurological and psychiatric disorders. Therefore, understanding the signals modulating the genesis of human dopaminergic neurons is crucial to elucidate di...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1152180/full |
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| author | Claire Boissart Marie Lasbareilles Marie Lasbareilles Marie Lasbareilles Johana Tournois Laure Chatrousse Thifaine Poullion Alexandra Benchoua Alexandra Benchoua |
| author_facet | Claire Boissart Marie Lasbareilles Marie Lasbareilles Marie Lasbareilles Johana Tournois Laure Chatrousse Thifaine Poullion Alexandra Benchoua Alexandra Benchoua |
| author_sort | Claire Boissart |
| collection | DOAJ |
| description | Introduction: Alteration in the development, maturation, and projection of dopaminergic neurons has been proposed to be associated with several neurological and psychiatric disorders. Therefore, understanding the signals modulating the genesis of human dopaminergic neurons is crucial to elucidate disease etiology and develop effective countermeasures.Methods: In this study, we developed a screening model using human pluripotent stem cells to identify the modulators of dopaminergic neuron genesis. We set up a differentiation protocol to obtained floorplate midbrain progenitors competent to produce dopaminergic neurons and seeded them in a 384-well screening plate in a fully automated manner.Results and Discussion: These progenitors were treated with a collection of small molecules to identify the compounds increasing dopaminergic neuron production. As a proof-of-principle, we screened a library of compounds targeting purine- and adenosine-dependent pathways and identified an adenosine receptor 3 agonist as a candidate molecule to increase dopaminergic neuron production under physiological conditions and in cells invalidated for the HPRT1 gene. This screening model can provide important insights into the etiology of various diseases affecting the dopaminergic circuit development and plasticity and be used to identify therapeutic molecules for these diseases. |
| first_indexed | 2024-03-13T03:12:32Z |
| format | Article |
| id | doaj.art-03e5a7a29fe64288bd3b0b58a5424789 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T03:12:32Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-03e5a7a29fe64288bd3b0b58a54247892023-06-26T10:32:50ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-06-011410.3389/fphar.2023.11521801152180Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principleClaire Boissart0Marie Lasbareilles1Marie Lasbareilles2Marie Lasbareilles3Johana Tournois4Laure Chatrousse5Thifaine Poullion6Alexandra Benchoua7Alexandra Benchoua8CECS, I-STEM, AFM, Neuroplasticity and Therapeutics, Corbeil-Essonnes, FranceCECS, I-STEM, AFM, Neuroplasticity and Therapeutics, Corbeil-Essonnes, FranceINSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes, FranceUEVE UMR 861, I-STEM, AFM, Corbeil-Essonnes, FranceCECS, I-STEM, AFM, Research and Technological Innovation, High Throughput Screening Plateform, Corbeil-Essonnes, FranceCECS, I-STEM, AFM, Neuroplasticity and Therapeutics, Corbeil-Essonnes, FranceCECS, I-STEM, AFM, Neuroplasticity and Therapeutics, Corbeil-Essonnes, FranceCECS, I-STEM, AFM, Neuroplasticity and Therapeutics, Corbeil-Essonnes, FranceCECS, I-STEM, AFM, Research and Technological Innovation, High Throughput Screening Plateform, Corbeil-Essonnes, FranceIntroduction: Alteration in the development, maturation, and projection of dopaminergic neurons has been proposed to be associated with several neurological and psychiatric disorders. Therefore, understanding the signals modulating the genesis of human dopaminergic neurons is crucial to elucidate disease etiology and develop effective countermeasures.Methods: In this study, we developed a screening model using human pluripotent stem cells to identify the modulators of dopaminergic neuron genesis. We set up a differentiation protocol to obtained floorplate midbrain progenitors competent to produce dopaminergic neurons and seeded them in a 384-well screening plate in a fully automated manner.Results and Discussion: These progenitors were treated with a collection of small molecules to identify the compounds increasing dopaminergic neuron production. As a proof-of-principle, we screened a library of compounds targeting purine- and adenosine-dependent pathways and identified an adenosine receptor 3 agonist as a candidate molecule to increase dopaminergic neuron production under physiological conditions and in cells invalidated for the HPRT1 gene. This screening model can provide important insights into the etiology of various diseases affecting the dopaminergic circuit development and plasticity and be used to identify therapeutic molecules for these diseases.https://www.frontiersin.org/articles/10.3389/fphar.2023.1152180/fullPurinesLesch–Nyhan diseasedopaminepluripotent stem cellshigh-throughput screeningdrug discovery |
| spellingShingle | Claire Boissart Marie Lasbareilles Marie Lasbareilles Marie Lasbareilles Johana Tournois Laure Chatrousse Thifaine Poullion Alexandra Benchoua Alexandra Benchoua Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle Frontiers in Pharmacology Purines Lesch–Nyhan disease dopamine pluripotent stem cells high-throughput screening drug discovery |
| title | Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle |
| title_full | Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle |
| title_fullStr | Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle |
| title_full_unstemmed | Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle |
| title_short | Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle |
| title_sort | identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell based high throughput screening automated system purinergic pathways as a proof of principle |
| topic | Purines Lesch–Nyhan disease dopamine pluripotent stem cells high-throughput screening drug discovery |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1152180/full |
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