Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation
Cockayne syndrome (CS) is a severe neurodevelopmental disorder characterized by growth abnormalities, premature aging, and photosensitivity. Mutation of Cockayne syndrome B (CSB) affects neuronal gene expression and differentiation, so we attempted to bypass its function by expressing downstream tar...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716301723 |
| _version_ | 1818701259390058496 |
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| author | Yuming Wang Jace Jones-Tabah Probir Chakravarty Aengus Stewart Alysson Muotri Rebecca R. Laposa Jesper Q. Svejstrup |
| author_facet | Yuming Wang Jace Jones-Tabah Probir Chakravarty Aengus Stewart Alysson Muotri Rebecca R. Laposa Jesper Q. Svejstrup |
| author_sort | Yuming Wang |
| collection | DOAJ |
| description | Cockayne syndrome (CS) is a severe neurodevelopmental disorder characterized by growth abnormalities, premature aging, and photosensitivity. Mutation of Cockayne syndrome B (CSB) affects neuronal gene expression and differentiation, so we attempted to bypass its function by expressing downstream target genes. Intriguingly, ectopic expression of Synaptotagmin 9 (SYT9), a key component of the machinery controlling neurotrophin release, bypasses the need for CSB in neuritogenesis. Importantly, brain-derived neurotrophic factor (BDNF), a neurotrophin implicated in neuronal differentiation and synaptic modulation, and pharmacological mimics such as 7,8-dihydroxyflavone and amitriptyline can compensate for CSB deficiency in cell models of neuronal differentiation as well. SYT9 and BDNF are downregulated in CS patient brain tissue, further indicating that sub-optimal neurotrophin signaling underlies neurological defects in CS. In addition to shedding light on cellular mechanisms underlying CS and pointing to future avenues for pharmacological intervention, these data suggest an important role for SYT9 in neuronal differentiation. |
| first_indexed | 2024-12-17T15:18:00Z |
| format | Article |
| id | doaj.art-2a1fa791113c4b3e99e593e069351594 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-17T15:18:00Z |
| publishDate | 2016-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2a1fa791113c4b3e99e593e0693515942022-12-21T21:43:28ZengElsevierCell Reports2211-12472016-03-0114112554256110.1016/j.celrep.2016.02.051Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal DifferentiationYuming Wang0Jace Jones-Tabah1Probir Chakravarty2Aengus Stewart3Alysson Muotri4Rebecca R. Laposa5Jesper Q. Svejstrup6Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms, Hertfordshire EN6 3LD, UKDepartment of Pharmacology and Toxicology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, CanadaBioinformatics & Biostatistics Group, The Francis Crick Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UKBioinformatics & Biostatistics Group, The Francis Crick Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UKDepartment of Pediatrics, University of California, San Diego, 2800 Torrey Pines Scenic Drive, La Jolla, CA 92037, USADepartment of Pharmacology and Toxicology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, CanadaMechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms, Hertfordshire EN6 3LD, UKCockayne syndrome (CS) is a severe neurodevelopmental disorder characterized by growth abnormalities, premature aging, and photosensitivity. Mutation of Cockayne syndrome B (CSB) affects neuronal gene expression and differentiation, so we attempted to bypass its function by expressing downstream target genes. Intriguingly, ectopic expression of Synaptotagmin 9 (SYT9), a key component of the machinery controlling neurotrophin release, bypasses the need for CSB in neuritogenesis. Importantly, brain-derived neurotrophic factor (BDNF), a neurotrophin implicated in neuronal differentiation and synaptic modulation, and pharmacological mimics such as 7,8-dihydroxyflavone and amitriptyline can compensate for CSB deficiency in cell models of neuronal differentiation as well. SYT9 and BDNF are downregulated in CS patient brain tissue, further indicating that sub-optimal neurotrophin signaling underlies neurological defects in CS. In addition to shedding light on cellular mechanisms underlying CS and pointing to future avenues for pharmacological intervention, these data suggest an important role for SYT9 in neuronal differentiation.http://www.sciencedirect.com/science/article/pii/S2211124716301723 |
| spellingShingle | Yuming Wang Jace Jones-Tabah Probir Chakravarty Aengus Stewart Alysson Muotri Rebecca R. Laposa Jesper Q. Svejstrup Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation Cell Reports |
| title | Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation |
| title_full | Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation |
| title_fullStr | Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation |
| title_full_unstemmed | Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation |
| title_short | Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation |
| title_sort | pharmacological bypass of cockayne syndrome b function in neuronal differentiation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716301723 |
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