title: Nontelomeric splice variant of telomere repeat-binding factor 2 maintains neuronal traits by sequestering repressor element 1-silencing transcription factor.
abstract: Telomere repeat-binding factor 2 (TRF2) is critical for telomere integrity in dividing stem and somatic cells, but its role in postmitotic neurons is unknown. Apart from protecting telomeres, nuclear TRF2 interacts with the master neuronal gene-silencer repressor element 1-silencing transcription factor (REST), and disruption of this interaction induces neuronal differentiation. Here we report a developmental switch from the expression of TRF2 in proliferating neural progenitor cells to expression of a unique short nontelomeric isoform of TRF2 (TRF2-S) as neurons establish a fully differentiated state. Unlike nuclear TRF2, which enhances REST-mediated gene repression, TRF2-S is located in the cytoplasm where it sequesters REST, thereby maintaining the expression of neuronal genes, including those encoding glutamate receptors, cell adhesion, and neurofilament proteins. In neurons, TRF2-S-mediated antagonism of REST nuclear activity is greatly attenuated by either overexpression of TRF2 or administration of the excitatory amino acid kainic acid. Overexpression of TRF2-S rescues kainic acid-induced REST nuclear accumulation and its gene-silencing effects. Thus, TRF2-S acts as part of a unique developmentally regulated molecular switch that plays critical roles in the maintenance and plasticity of neurons.
authors: Laboratories of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA
authors: Peisu
authors: P
authors: Zhang
authors: Rebecca
authors: R
authors: Casaday-Potts
authors: Patricia
authors: P
authors: Precht
authors: Haiyang
authors: H
authors: Jiang
authors: Yie
authors: Y
authors: Liu
authors: Michael J
authors: MJ
authors: Pazin
authors: Mark P
authors: MP
authors: Mattson
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology*; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016615:Telomere; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; D034501:Telomere-Binding Proteins; D014157:Transcription Factors