title: Bex3 Dimerization Regulates NGF-Dependent Neuronal Survival and Differentiation by Enhancing trkA Gene Transcription.
abstract: The development of the nervous system is a temporally and spatially coordinated process that relies on the proper regulation of the genes involved. Neurotrophins and their receptors are directly responsible for the survival and differentiation of sensory and sympathetic neurons; however, it is not fully understood how genes encoding Trk neurotrophin receptors are regulated. Here, we show that rat Bex3 protein specifically regulates TrkA expression by acting at the trkA gene promoter level. Bex3 dimerization and shuttling to the nucleus regulate the transcription of the trkA promoter under basal conditions and also enhance nerve growth factor (NGF)-mediated trkA promoter activation. Moreover, qChIP assays indicate that Bex3 associates with the trkA promoter within a 150 bp sequence, immediately upstream from the transcription start site, which is sufficient to mediate the effects of Bex3. Consequently, the downregulation of Bex3 using shRNA increases neuronal apoptosis in NGF-dependent sensory neurons deprived of NGF and compromises PC12 cell differentiation in response to NGF. Our results support an important role for Bex3 in the regulation of TrkA expression and in NGF-mediated functions through modulation of the trkA promoter.
authors.affiliation: Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain, and.
authors.forename: Laura
authors.initials: L
authors.lastname: Calvo
authors.affiliation: Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain, and.
authors.forename: Begoña
authors.initials: B
authors.lastname: Anta
authors.affiliation: Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain, and.
authors.forename: Saray
authors.initials: S
authors.lastname: López-Benito
authors.affiliation: Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain, and.
authors.forename: Carlos
authors.identifier: http://orcid.org/0000-0002-9621-2133
authors.initials: C
authors.lastname: Martín-Rodriguez
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, Cornell University, New York, New York 10065.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.affiliation: Instituto de Biología Funcional y Genómica, CSIC/Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Pilar
authors.identifier: http://orcid.org/0000-0003-3557-2247
authors.initials: P
authors.lastname: Pérez
authors.affiliation: Instituto de Biología Funcional y Genómica, CSIC/Universidad de Salamanca, 37007 Salamanca, Spain.
authors.forename: Dionisio
authors.identifier: http://orcid.org/0000-0002-2964-5414
authors.initials: D
authors.lastname: Martín-Zanca
authors.affiliation: Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL), and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain, and arevalojc@usal.es.
authors.forename: Juan C
authors.identifier: http://orcid.org/0000-0003-1994-3095
authors.initials: JC
authors.lastname: Arévalo
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D020917:Receptor, trkA / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C485843:Bex3 protein, rat; D020932:Nerve Growth Factor; D020917:Receptor, trkA
keywords: Bex3; NGF; TrkA; differentiation; gene promoter; transcription