RGS4
Regulator of G-protein signaling 4 (RGP4) (RGS4)
Publications[править]
In the normal brain, age is associated with changes in gene expression. Age is also a prominent risk factor for Alzheimer's disease (AD), where clinical features are similar to age-related decreases in cognitive performance. We hypothesized that some age-related changes in gene expression are accelerated in AD patients. To study this, we selected 10 candidate genes earlier shown by microarray analysis to be differentially expressed in AD (Emilsson et al., [2006] Neurobiol Dis 21:618-625). Using real-time PCR analysis and a control based statistical model, we investigated age-related changes in mRNA levels in a large collection of human brain postmortem tissues from AD patients and controls. Our results demonstrate that the age-related changes in gene expression are manifested earlier in AD. Furthermore, five of the genes (ITPKB, RGS4, RAB3A, STMN1, SYNGR3) have in common an involvement in neuronal calcium dependent signaling, a cellular process previously related to both AD and aging. These observations suggest that coordinated transcriptional changes associated with ageing and calcium homeostasis in the human brain are accelerated in patients with AD. Our results point to the possibility that the activity of these genes can be used in the future as a palette of biomarkers for predicting disease risk in young individuals.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- Humans
- Male
- Membrane Proteins
- Middle Aged
- Nerve Tissue Proteins
- Oligonucleotide Array Sequence Analysis
- Phosphotransferases (Alcohol Group Acceptor)
- RGS Proteins
- Stathmin
- Synaptogyrins
- rab3A GTP-Binding Protein
Signaling through G-protein-coupled receptors is modulated by a family of regulator of G protein signaling (RGS) proteins that have been implicated in several neurological and psychiatric disorders. Defining the detailed expression patterns and developmental regulation of RGS proteins has been hampered by an absence of antibodies useful for mapping. We have utilized bacterial artificial chromosome (BAC) methods to create transgenic mice that express GFP under the control of endogenous regulator of G-protein signaling 4 (RGS4) enhancer elements. This report focuses on expression patterns in the developing and mature cerebral cortex. Based on reporter distribution, RGS4 is expressed by birth in neurons across all cortical domains, but in different patterns that suggest region- and layer-specific regulation. Peak expression typically occurs before puberty, with complex down-regulation by adulthood. Deep and superficial neurons, in particular, vary in their patterns across developmental age and region and, in primary sensory cortices, layer IV neurons exhibit low or no expression of the GFP reporter. These data suggest that altering RGS4 function will produce a complex neuronal phenotype with cell- and subdomain-specificity in the cerebral cortex.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Cell Differentiation
- Cell Movement
- Cell Proliferation
- Cerebral Cortex
- Chromosomes, Artificial, Bacterial
- Enhancer Elements, Genetic
- Gene Expression Regulation, Developmental
- Genes, Reporter
- Green Fluorescent Proteins
- Mice
- Mice, Transgenic
- Molecular Biology
- Neural Pathways
- Neurons
- Phenotype
- RGS Proteins
- Stem Cells
- Transgenes
A large family of regulator of G protein signaling (RGS) proteins modulates signaling through G-protein-coupled receptors. Previous studies have implicated RGS4 as a vulnerability gene in schizophrenia. To begin to understand structure-function relationships, we have utilized bacterial artificial chromosome (BAC) methods to create transgenic mice that express green fluorescent protein (GFP) under the control of endogenous RGS4 enhancer elements, circumventing the lack of suitable antibodies for analysis of dynamic patterns of expression. This report follows from the accompanying mapping paper in cerebral cortex, with a focus on developmental and mature expression patterns in subcortical telencephalic, diencephalic and brainstem areas. Based on reporter distribution, the data suggest that alterations in RGS4 function will engender a complex phenotype of increased and decreased neuronal output, with developmental, regional, and cellular specificity.
MeSH Terms
- Aging
- Animals
- Brain
- Cell Differentiation
- Cell Movement
- Cell Proliferation
- Chromosomes, Artificial, Bacterial
- Enhancer Elements, Genetic
- Gene Expression Regulation, Developmental
- Genes, Reporter
- Green Fluorescent Proteins
- Mice
- Mice, Transgenic
- Molecular Biology
- Neural Pathways
- Neurons
- Phenotype
- RGS Proteins
- Stem Cells
- Transgenes
The abundant expression of RGS (regulator of G-protein signalling) proteins in neurons, together with their modulatory function on G-protein-dependent neurotransmission, provides the basis for cellular adaptation to sensory inputs. To identify the molecular mechanism involved in the sensory experience-induced neural development, we performed a systematic survey of the localization of mRNAs encoding three subtypes of the RGSs (RGS2, RGS4 and RGS7) in developing rat brains by in situ hybridization through postnatal day 2 (P2), P10 and P18 to adult. The most dramatic changes of expression patterns were observed in the discrete neuronal cell layers of the cerebral neocortex (for RGS2 and 4), the hippocampus (for RGS2, 4 and 7), the thalamus (for RGS4) and the cerebellum (for RGS2 and 7). In the neocortex, RGS2 mRNA was enriched in the superficial cortical plate at P2, in contrast to RGS4, which was enriched in more mature neurons of the deeper layer V and VI. In the hippocampus, the neuronal cell layer-specific expression pattern of RGS2 developed from P2 to P18. RGS4 expression was temporarily confined to the CA pyramidal cell layer and not detectable in the dentate gyrus at P10 and P18. Similarly, a high level of expression of RGS7 was observed in the CA area, but not in the dentate gyrus at P2 and P10. In the cerebellum, the maturation of laminar expression patterns for the three RGSs correlated with neuronal maturation and synaptogenesis at P18. The most characteristic temporal pattern among the three RGSs was observed for RGS4 mRNA, which was highly enriched in the thalamocortical regions. The peaks of RGS4 expression were seen in the following regions with distinct onset and duration: the neocortex (from P2 onward), the hippocampus (P10 and P18) and the thalamus (from P18 onward). The divergent temporal and spatial expression of RGS subtypes and their dynamic control in the cortex, the hippocampus and the thalamus suggest that the RGS family could play multiple distinct roles in experience-dependent brain development.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Brain
- Cell Differentiation
- Female
- GTP-Binding Proteins
- Gene Expression Regulation, Developmental
- Male
- Neuronal Plasticity
- Neurons
- RGS Proteins
- RNA, Messenger
- Rats
- Rats, Inbred F344
- Rats, Sprague-Dawley
- Sensation
- Synaptic Transmission