Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation
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Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation. / Wang, Yuming; Jones-Tabah, Jace; Chakravarty, Probir; Stewart, Aengus; Muotri, Alysson; Laposa, Rebecca R.; Svejstrup, Jesper Q.
I: Cell Reports, Bind 14, Nr. 11, 2016, s. 2554-2561.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation
AU - Wang, Yuming
AU - Jones-Tabah, Jace
AU - Chakravarty, Probir
AU - Stewart, Aengus
AU - Muotri, Alysson
AU - Laposa, Rebecca R.
AU - Svejstrup, Jesper Q.
N1 - Funding Information: This work was supported by a grant from the European Research Council and by the Francis Crick Institute (grant number FCI01), which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. The NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland, Baltimore (member of NIH NBB) kindly provided brain tissue samples. The Crick Institute’s Advanced Sequencing Facility and the Cell Services Facility are thanked for their expert assistance. Giampietro Schiavo, P.J. Brooks, Peter Verrijzer, Laura Williamson, Michael Lim, and Barbara Dirac-Svejstrup are thanked for comments. Publisher Copyright: © 2016 The Authors.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2016.02.051
DO - 10.1016/j.celrep.2016.02.051
M3 - Journal article
C2 - 26972010
AN - SCOPUS:84959893357
VL - 14
SP - 2554
EP - 2561
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 11
ER -
ID: 330898436