A gene expression atlas of the central nervous system based on bacterial artificial chromosomes

Gong, Shiaoching; Chen, Zheng; Doughty, Martin L.; Losos, Kasia; Didkovsky, Nicholas; Schambra, Uta B.; Nowak, Norma J.; Joyner, Alexandra L.; Leblanc, Gabrielle G.; Hatten, Mary E.; Heintz, Nathaniel

doi:10.1038/nature02033

Cited by 1,952 publications

(1,962 citation statements)

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“…An alternative method is transgenic labeling of cells with a fluorescent reporter. We tested transgenic mice that expressed GFP under the control of the Dcx promoter (Dcx::EGFP 37 and unpublished), because this model should allow visualization of the whole population of migrating RMS neurons. Strong GFP signal was exclusively found in the SVZ, RMS and OB in both adult (not shown) and P5 (Fig.…”

Section: Novel Methods For Measuring Migration Within the Rmsmentioning

confidence: 99%

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

et al. 2006

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The ability of the mature mammalian nervous system to continually produce neuronal precursors is of considerable importance, as manipulation of this process might one day permit the replacement of cells lost as a result of injury or disease. In mammals, the anterior subventricular zone (SVZa) region is one of the primary sites of adult neurogenesis. Here we show that Doublecortin (DCX), a widely used marker for newly generated neurons, when deleted in mouse results in a severe morphological defect in the rostral migratory stream and delayed neuronal migration that is independent of direction or responsiveness to Slit chemorepulsion. DCX is required for nuclear translocation and maintenance of bipolar morphology during migration of these cells. Our data identifies a critical function for DCX in the movement of newly generated neurons in the adult brain.In the rodent and primate brain, the anterior region of the lateral ventricle and the hippocampus are the primary sites of adult neurogenesis [1][2][3][4][5][6][7] . These neuroblasts, upon completing migration, are capable of maturing into fully differentiated neurons, integrating into local synaptic circuits and may be important in adult cognitive processing [8][9][10][11] .The mechanisms controlling the targeted translocation of large numbers of cells to the olfactory bulb (OB) over a considerable distance (>5 mm in the adult mouse) are an issue of intense investigation. These neurons translocate using a process known as chain migration, whereby the cells use each other as the migratory substrate 12 . These newly generated neurons are derived from SVZa glial fibrillary acidic protein (GFAP)-positive astrocytes 13,14 , which also ensheath them as they move through extensive interconnected networks along the lining of the lateral ventricle in the rostral forebrain and the rostral migratory stream (RMS) 15 . There, they are under the control of extracellular migration guidance cues, including the secreted ligands Slit and Reelin [16][17][18][19] , the receptors ErbB4 and Deleted in Colorectal Carcinoma (DCC) 20,21 , as well as integrins and neural cell adhesion molecule [21][22][23] . Upon reaching the bulb, the neurons turn and migrate in a radial direction 24 , integrating into either the granule cell layer or the periglomerular network 25 . 3The X-linked gene doublecortin (DCX) is mutated in some patients with the severe neuronal migration defect called classical lissencephaly or double cortex syndrome 26,27 . This migration defect is likely to be cell autonomous, because in females with a heterozygous mutation, approximately half of the neurons are misplaced within the cerebral cortex as would be expected from random X-chromosome inactivation. As a result, males display a four-layered agyric cortex and females display a subcortical band of heterotopic neurons. It was surprising, therefore, that the Dcx knockout mice displayed no appreciable defect in cortical neuronal lamination or positioning 28 . One possible explanation for these species differences ...

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Section: Novel Methods For Measuring Migration Within the Rmsmentioning

confidence: 99%

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

et al. 2006

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“…In another effort using the egr-1/zif268 promoter to drive expression of a destabilized GFP in transgenic rats, fluorescence microscopy failed to detect any GFP signal, despite the presence of reporter transcript [4]. The GENSAT project, a consortium-based effort to create a library of GFP-transgenic mice driven by brain specific promoters, has also not been successful at producing animals showing detectable fluorescence that can be visualized without immunohistochemical amplification, most likely because levels of fluorescent protein expression remain too low for direct visualization [5]. However, this project has created egr1/ zif268, arc, and homer-GFP transgenic mice.…”

Section: Fluorescent Reporters Of Inducible Gene Expressionmentioning

confidence: 99%

Visualizing circuits and systems using transgenic reporters of neural activity

Barth

2007

Current Opinion in Neurobiology

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Genetically encoded sensors of neural activity enable visualization of circuit-level function in the central nervous system. Although our understanding of the molecular events that regulate neuronal firing, synaptic function, and plasticity has expanded rapidly over the past fifteen years, an appreciation for how cellular changes are functionally integrated at the circuit level has lagged. A new generation of tools that employ fluorescent sensors of neural activity promises unique opportunities to bridge the gap between cellular and system-levels analysis.This review will focus on genetically-encoded sensors. A primary advantage of these indicators is that they can be non-selectively introduced to large populations of cells using either transgenic or viral-mediated approaches. This ability removes the non-trivial obstacles of how to get chemical indicators into cells of interest, a problem that has dogged investigators who have been interested in mapping neural function in the intact CNS. Five different types of approaches and their relative utility will be reviewed here: 1) reporters of immediate-early gene (IEG) activation using promoters such as c-fos and arc, 2) voltage-based sensors, such as GFPcoupled Na + and K + channels, 3) Cl − based sensors, 4) Ca ++ -based sensors, such as Camgaroo and the troponin-based TN-L15, and 5) pH-based sensors, which have been particularly useful for examining synaptic activity of highly convergent afferents in sensory systems in vivo. Particular attention will be paid to reporters of IEG expression, since these tools employ the built-in threshold function that occurs with activation of gene expression, provoking new experimental questions by expanding the timescale of analysis for circuit and system-level functional mapping. Fluorescent reporters of inducible gene expressionImmediate-early gene expression (IEG) can be a reliable marker of elevated neuronal firing, reporting activity over time scales that range from minutes to hours compared to ms and seconds for voltage-or ion-based sensors. In ion-based approaches, indicators are constitutively present in the cell, and the fluorescent protein must be engineered to be a sensor with rapid onset and offset kinetics to achieve temporal fidelity with the process being measured. In contrast, monitoring IEG expression can be directly coupled to transcription of the reporter gene. However, because maturation of the fluorophore is required for detection, a temporal delay may be introduced into reporter detection. This delay in reporting activity is advantageous in that it expands the types of experimental questions that can be addressed. For example, do IEGexpressing cells remain more excitable after stimulus cessation? Are cells activated by two temporally distinct stimuli (i.e. training and recall in a memory task) overlapping or distinct?

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“…Despite these difficulties, recently developed bacterial artificial chromosome (BAC) transgenic mice expressing enhanced green fluorescent protein (EGFP) enable the examination of gene expression in these two distinct striatal neurons (Durieux et al, 2011;Ena et al, 2011;Gong et al, 2003;Surmeier et al, 2007). Morphologically indistinguishable striatopallidal and striatonigral neuronal subtypes comprise approximately 90-95% of striatal neurons (Graybiel, 2000;Humphries and Prescott, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Striatopallidal neurons, which project to the ventral pallidum or globus pallidus, can be identified by the dopamine D2 receptor (D2R). In contrast, striatonigral neurons, which project axons to the substantia nigra pars reticulata, can be recognized by the cholinergic muscarinic M4 receptor (M4R) or dopamine D1 receptor (D1R) (Gong et al, 2003;Le Moine and Bloch, 1995;Lobo et al, 2006;Surmeier et al, 1996). This is especially important as striatal-specific neuronal circuits are implicated in several aspects of addictive behaviors (Koob and Volkow, 2010).…”

Section: Introductionmentioning

confidence: 99%

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

Nam

Bruner

Choi

2013

Molecules and Cells

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Adenosine signaling has been implicated in the pathophysiology of alcohol use disorders and other psychiatric disorders such as anxiety and depression. Numerous studies have indicated a role for A1 receptors (A1R) in acute ethanol-induced motor incoordination, while A2A receptors (A2AR) mainly regulate the rewarding effect of ethanol in mice. Recent findings have demonstrated that dampened A2AR-mediated signaling in the dorsomedial striatum (DMS) promotes ethanol-seeking behaviors. Moreover, decreased A2AR function is associated with decreased CREB activity in the DMS, which enhances goal-oriented behaviors and contributes to excessive ethanol drinking in mice. Interestingly, caffeine, the most commonly used psychoactive substance, is known to inhibit both the A1R and A2AR. This dampened adenosine receptor function may mask some of the acute intoxicating effects of ethanol. Furthermore, based on the fact that A2AR activity plays a role in goal-directed behavior, caffeine may also promote ethanol-seeking behavior. The A2AR is enriched in the striatum and exclusively expressed in striatopallidal neurons, which may be responsible for the regulation of inhibitory behavioral control over drug rewarding processes through the indirect pathway of the basal ganglia circuit. Furthermore, the antagonistic interactions between adenosine and dopamine receptors in the striatum also play an integral role in alcoholism and addiction-related disorders. This review focuses on regulation of adenosine signaling in striatal circuits and the possible implication of caffeine in goal-directed behaviors and addiction.

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A gene expression atlas of the central nervous system based on bacterial artificial chromosomes

Cited by 1,952 publications

References 42 publications

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

Visualizing circuits and systems using transgenic reporters of neural activity

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

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