Upregulation of Insulin-Like Growth Factor Binding Protein 3 in Astrocytes of Transgenic Mice That Express Borna Disease Virus Phosphoprotein

Abstract

In a previous study, we demonstrated that transgenic mice that express Borna disease virus (BDV) phosphoprotein (P) in astrocytes show striking neurobehavioral abnormalities resembling those in BDV-infected animals. To understand the molecular disturbances induced by the expression of P in astrocytes, we performed microarray analysis with cultured astroglial cells transiently expressing P. We showed that expression of insulin-like growth factor binding protein 3 mRNA increases not only in P-expressing cultured cells but also in astrocytes from the cerebella of P transgenic mice (P-Tg). Furthermore, we demonstrated that insulin-like growth factor signaling is disturbed in the P-Tg cerebellum, a factor that might be involved in the increased vulnerability of Purkinje cell neurons in the brain.Borna disease virus (BDV) is a highly neurotropic negativestranded RNA virus that belongs to the order Mononegavirales. Many studies have demonstrated that natural infections with BDV occur worldwide in a variety of vertebrate species, suggesting that the host range of the virus includes all warmblooded animals (12). BDV persistently infects the central nervous systems (CNSs) of many animal species and causes neurobehavioral disorders such as anxiety, aggression, hyperactivity, abnormal play behavior, and cognitive deficits (6,20). Previous studies have demonstrated that BDV infection in the rat model induces autism-like neurodevelopmental and behavioral disturbances without the characteristic inflammatory responses in the brain (6,12,19). Therefore, studies of this virus infection in animals could provide a valuable model to investigate the neuropathology of behavioral and neurodevelopmental disorders (1,18,19).In a previous study, we reported the generation of transgenic mice expressing BDV phosphoprotein (P) selectively in astrocytes (8). These transgenic mice (P-Tg) showed striking neurobehavioral abnormalities that resemble those described for BDV-infected animals, such as enhanced intermale aggressiveness, hyperactivity, and spatial reference memory deficit (8). Furthermore, P-Tg exhibited abnormalities in the expression of neurotropic factors and neurotransmitters, as well as in synaptic density. The study provided a novel approach to understanding not only the link between viral infection and neurobehavioral disorders but also the relationship between neurobehavioral disorders and astrocyte dysfunctions (26,29).In an effort to understand the molecular disturbances of glial cells triggered by the expression of BDV P, we performed microarray analysis with C6 rat glioma cells expressing either green fluorescent protein (GFP) (C6-GFP cells) or BDV P (C6-P cells), using Agilent's whole rat genome DNA array, in which 41,090 different cDNA probes are spotted on glass slides. cDNA was generated from both cell lines at 1 week postelectroporation and hybridized to microarrays. Affected genes in BDV P-expressing C6 rat glioma cells were extracted using GeneSpring software (P-value cutoff of Ͻ0.01), and we found that the expressi...

A comparative transcriptomic analysis of astrocytes differentiation from human neural progenitor cells

“…C and Supporting Information Table S2). Among the most upregulated (log2 fc > 1.5) and most abundantly expressed genes, (FPKM > 30) we found several genes expressed by astrocytes in normal or pathological conditions, such as CD44 (Hernandez et al ., ), PODXL (Wu et al ., ), SPARCL1 (Kucukdereli et al ., ), ELN (Hernandez et al ., ), SOCS3 (Okada et al ., ), CCL2 (Lo et al ., ) and IGFBP3(Honda et al ., ). Astrocytes play important roles in synapses formation, maturation and maintenance through the secretion of different proteins including glypicans (GPC4) and hevin (SPARCL1), and these two genes were enriched in CNTF/BMP4‐astrocytes (Kucukdereli et al ., ; Allen et al ., ).…”

Comprehensive analysis of endogenous bornavirus-like elements in eukaryote genomes

“…However, because P was identified as a BDV pathogenic factor, expression of integrated P may have adverse effects on host animals. In fact, transgenic mice expressing BDV N protein do not show any sign of neuronal disease, whereas abnormal behaviour has been observed in BDV P transgenic mice [6,7,66]. Therefore, integration and expression of a P-like protein might have an adverse effect, producing a survival disadvantage for a host animal.…”

“…N encapisidates the viral RNA to form the viral nucleocapsid. P is a cofactor of viral polymerase L and is also a phosphorylation decoy involved in BDV pathogenicity [6][7][8][9][10][11][12][13]. Viral gene products N, P and L are the minimal components of viral ribonucleoprotein (vRNP) [14].…”

Nucleocytoplasmic Shuttling of Viral Proteins in Borna Disease Virus Infection

“…However, in contrast to other viral phosphoproteins, the co-factor activity of P for BDV RdRp is negatively regulated by phosphorylation [23]. P is efficiently transported to the nucleus and is localized in the nuclei of transgenic mice expressing P selectively in astrocytes [24,25]. P contains two NLSs at the N- and C-termini (P 29 RPRKIPR 36 and P 181 PRIYPQLPSAPT 193 , respectively) [26,27].…”