title: Chronic HIV-1 Tat and HIV reduce Rbfox3/NeuN: evidence for sex-related effects.
abstract: The NeuN antibody has been widely used to identify and quantify neurons in normal and disease situations based on binding to a nuclear epitope in most types of neurons. This epitope was recently identified as the RNA-binding, feminizing locus on X-3 (Rbfox3), a member of the larger, mammalian Fox1 family of RNA binding proteins. Fox1 proteins recognize a unique UGCAUG mRNA motif and regulate alternative splicing of precursor mRNA to control post-transcriptional events important in neuronal differentiation and central nervous system development. Recent clinical findings show that Rbfox3/NeuN gene dosage is altered in certain human neurodevelopmental disorders, and redistribution has been noted in HIV(+) tissue. We hypothesized that HIV-1 Tat might affect Rbfox3/NeuN expression, and examined this question in vivo using inducible transgenic mice, and in vitro using human mesencephalic-derived neurons. Rbfox3/NeuN expression and localization in HIV+ basal ganglia and hippocampus was also examined. Chronic Tat exposure reduced Rbfox3/NeuN protein levels and increased cytoplasmic localization, similar to the effect of HIV exposure. Cytoplasmic Rbfox3/NeuN signal has occasionally been reported, although the meaning or function of cytoplasmic versus nuclear localization remains speculative. Importantly, Rbfox3/NeuN reductions were more significant in male mice. Although Rbfox3/NeuN-expressing cells were significantly decreased by Tat exposure, stereology showed that Nissl(+) neuron numbers remained normal. Thus, loss of Rbfox3/NeuN may relate more to functional change than to neuron loss. The effects of Tat by itself are highly relevant to HIV(+) individuals maintained on antiretroviral therapy, since Tat is released from infected cells even when viral replication is inhibited.
authors.affiliation: Department of Anatomy & Neurobiology, MCV Campus, Virginia Commonwealth University, P.O. Box 980709, Richmond, VA 23298-0709, USA. hahnyk@vcu.edu.
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Hahn
authors.forename: Ruturaj R
authors.initials: RR
authors.lastname: Masvekar
authors.forename: Ruqiang
authors.initials: R
authors.lastname: Xu
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D001479:Basal Ganglia / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; C506808:neuronal nuclear antigen NeuN, human; D054322:tat Gene Products, Human Immunodeficiency Virus