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 -