title: An RNA binding protein promotes axonal integrity in peripheral neurons by destabilizing REST.
abstract: The RE1 Silencing Transcription Factor (REST) acts as a governor of the mature neuronal phenotype by repressing a large consortium of neuronal genes in non-neuronal cells. In the developing nervous system, REST is present in progenitors and downregulated at terminal differentiation to promote acquisition of mature neuronal phenotypes. Paradoxically, REST is still detected in some regions of the adult nervous system, but how REST levels are regulated, and whether REST can still repress neuronal genes, is not known. Here, we report that homeostatic levels of REST are maintained in mature peripheral neurons by a constitutive post-transcriptional mechanism. Specifically, using a three-hybrid genetic screen, we identify the RNA binding protein, ZFP36L2, associated previously only with female fertility and hematopoiesis, and show that it regulates REST mRNA stability. Dorsal root ganglia in Zfp36l2 knock-out mice, or wild-type ganglia expressing ZFP36L2 shRNA, show higher steady-state levels of Rest mRNA and protein, and extend thin and disintegrating axons. This phenotype is due, at least in part, to abnormally elevated REST levels in the ganglia because the axonal phenotype is attenuated by acute knockdown of REST in Zfp36l2 KO DRG explants. The higher REST levels result in lower levels of target genes, indicating that REST can still fine-tune gene expression through repression. Thus, REST levels are titrated in mature peripheral neurons, in part through a ZFP36L2-mediated post-transcriptional mechanism, with consequences for axonal integrity.
authors.affiliation: Howard Hughes Medical Institute, Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cargnin
authors.affiliation: Howard Hughes Medical Institute, Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Tamilla
authors.initials: T
authors.lastname: Nechiporuk
authors.affiliation: Howard Hughes Medical Institute, Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Karin
authors.initials: K
authors.lastname: Müllendorff
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, and.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Stumpo
authors.affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, and.
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Blackshear
authors.affiliation: Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, New York 11794.
authors.forename: Nurit
authors.initials: N
authors.lastname: Ballas
authors.affiliation: Howard Hughes Medical Institute, Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, mandelg@ohsu.edu.
authors.forename: Gail
authors.initials: G
authors.lastname: Mandel
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016716:PC12 Cells; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D051816:Tristetraprolin / Q000096:biosynthesis* / Q000235:genetics; D000099229:RE1-Silencing Transcription Factor
chemical_list: D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D051816:Tristetraprolin; D000099229:RE1-Silencing Transcription Factor; C497553:Zfp36 protein, mouse
keywords: REST; RNA binding protein; ZFP36L2; axonal integrity; peripheral nervous system; post-transcriptional regulation