BAC Transgenic Mice and the GENSAT Database of Engineered Mouse Strains

Schmidt, Eric F.; Kus, Laura; Gong, Shiaoching; Heintz, Nathaniel

doi:10.1101/pdb.top073692

Cited by 63 publications

(61 citation statements)

References 32 publications

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“…C57BL/6J mice (The Jackson Laboratory) were utilized for Npas2 knock-down, gene expression, and ChIP studies. GENSAT Drd1-GFP mice (Tg(Drd1a-EGFP)X60Gsat) (26, 27) used for FACS sorting were obtained from Jackson labs. All mice were group housed in a 12/12 light/dark (LD) cycle (lights on at 7am, lights off at 7pm) with food and water ad libitum .…”

Section: Methodsmentioning

confidence: 99%

Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2

Ozburn

Falcón

Twaddle

et al. 2015

Biological Psychiatry

119

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Background Circadian gene disruptions are associated with the development of psychiatric disorders, including addiction. However, the mechanisms by which circadian genes regulate drug reward remain poorly understood. Methods We used mice with a mutation in Npas2, and AAV-shRNA mediated knock-down of Npas2 and Clock in the nucleus accumbens (NAc). We performed conditioned place preference (CPP) assays for cocaine. We utilized cell sorting techniques, qPCR and chromatin immunoprecipitation (ChIP) assays followed by deep sequencing (ChIP-seq). Results Npas2 mutants exhibit decreased sensitivity to cocaine reward which can be recapitulated with a knock-down of NPAS2 specifically in the NAc, demonstrating the functional importance of NPAS2 in this region. Interestingly, reducing CLOCK (a homologue of NPAS2) expression in the NAc had no effect, suggesting an important distinction in NPAS2 and CLOCK function. Furthermore, we find that NPAS2 expression is restricted to Drd1 expressing neurons, (i.e. “direct” pathway circuitry) while CLOCK is ubiquitous. Moreover, NPAS2 and CLOCK have distinct temporal patterns of DNA binding, and we identified novel and unique binding sites for each protein. We identified the Drd3 dopamine receptor as a direct transcriptional target of NPAS2 and find that NPAS2 knock-down in the NAc disrupts its diurnal rhythm in expression. Chronic cocaine treatment likewise disrupts the normal rhythm in Npas2 and Drd3 expression in the NAc, which may underlie behavioral plasticity in response to cocaine. Conclusions Together, these findings identify an important and novel role for the circadian protein, NPAS2, in the NAc in the regulation of dopamine receptor expression and drug reward.

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Section: Methodsmentioning

confidence: 99%

Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2

Ozburn

Falcón

Twaddle

et al. 2015

Biological Psychiatry

119

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“…All animals were of a mixed genetic background of C57BL/6J ϫ FVB/NJ ϫ 129 (19). TAC2-enhanced green fluorescent protein (GFP) mice (37) were kindly provided by Dr. Martin Myers.…”

Section: Methodsmentioning

confidence: 99%

Agouti-related peptide plays a critical role in leptin's effects on female puberty and reproduction

Sheffer-Babila

Sun

Israel

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Deficient leptin signaling causes infertility via reduced activity of GnRH neurons, causing a hypogonadal state in both rodents and humans. Because GnRH neurons do not express leptin receptors, leptin's effect on GnRH neurons must be indirect. Neurons within the hypothalamic arcuate nucleus that coexpress AGRP and NPY are considered to be important intermediate neurons involved in leptin regulation of GnRH neurons. Previously, we reported that the absence of AGRP and haploinsufficiency of MC4R in leptin receptor mutant (Lepr db/db ) females result in restoration of fertility and lactation despite the persistence of obesity and insulin resistance. The overarching hypothesis in the present study is that the absence or reduction of leptin's inhibition of AGRP/NPY neurons leads to suppression of GnRH release in cases of leptin signaling deficiency. Since TAC2 (NKB)-TAC3R signaling plays a role in puberty maturation and is modulated by metabolic status, the other aim of this study is to test whether TAC2/NKB neurons in ARC regulated by melanocortinergic signals herein affect leptin's action on puberty and reproduction. Our data showed that AGRP deficiency in Lepr db/db females restores normal timing of vaginal opening and estrous cycling, although uterine weight gain and mammary gland development are morphologically delayed. Nonetheless, Agrp Ϫ/Ϫ Lepr db/db females are fertile and sustain adequate nutrition of pups with lactation to weaning age. AGRP deficiency results in advanced vaginal opening in wild-type female mice. The postpubertal increase in hypothalamic TAC2 mRNA was not observed in Lepr db/db females, whereas AGRP deficiency restored it in Lepr db/db females. Additionally, MC4R activation with MTII induced FOS expression in TAC2 neurons, supporting the concept of melanocortinergic regulation of TAC2 neurons. These studies suggest that AGRP imposes an inhibitory effect on puberty and that TAC2 neurons may transmit melanocortinergic inhibition of GnRH neurons.agouti-related peptide; leptin; puberty; reproduction THE ONSET OF PUBERTY is the culmination of a subtle shift in balance of stimulatory and inhibitory neurotransmission within a complex neural network. Whereas the intrinsic pulsatility of GnRH neurons points toward a cell-autonomous function of gonadotropin-releasing hormone (GnRH) secretion, extrinsic signals are likely to be required to trigger activity in quiescent GnRH neurons. There is undoubtedly a link between metabolic status and GnRH activity (34). In the context of normal leptin signaling, a role has been implicated on the basis of a direct correlation between puberty onset and body weight (8, 16). Additionally, cases of defective leptin signaling in both humans and rodents result in hypogonadotropic hypogonadism (13). In a case report of a girl with leptin deficiency, treatment with leptin appeared to reverse the hypogonadal state (12). In cases of lipodystrophy with attendant hypoleptinemia, leptin therapy normalized pituitary hormone release (29) and restored menstrual cycles to all treat...

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“…We sought to optimize axonal growth potential, sensitivity of detection of functional locomotor improvement, and capacity to utilize genetic tools by establishing a cervical bridge implantation model in the mouse, and testing regeneration in transgenic mice expressing Crym:GFP in descending fiber tracts in the spinal cord. Mu-Crystallin (Crym) is expressed in a diverse array of tissues, including brain, where it is heavily localized within the descending projection neurons of the motor cortex [39-41]. After establishing evidence of bridge apposition and axonal regeneration in our mouse cervical SCI implantation model, and characterizing the specificity of Crym:GFP reporter expression in the spinal cord, we investigated the regeneration of descending axons into and beyond implanted PLG multichannel bridges.…”

Section: Introductionmentioning

confidence: 99%

Biomaterial bridges enable regeneration and re-entry of corticospinal tract axons into the caudal spinal cord after SCI: Association with recovery of forelimb function

et al. 2015

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a b s t r a c t Severed axon tracts fail to exhibit robust or spontaneous regeneration after spinal cord injury (SCI).Regeneration failure reflects a combination of factors, including the growth state of neuronal cell bodies and the regeneration-inhibitory environment of the central nervous system. However, while spared circuitry can be retrained, target reinnervation depends on longitudinally directed regeneration of transected axons. This study describes a biodegradable implant using poly(lactide-co-glycolide) (PLG) bridges as a carrier scaffold to support regeneration after injury. In order to detect regeneration of descending neuronal tracts into the bridge, and beyond into intact caudal parenchyma, we developed a mouse cervical implantation model and employed Crym:GFP transgenic mice. Characterization of Crym:GFP mice revealed that descending tracts, including the corticospinal tract, were labeled by green fluorescent protein (GFP), while ascending sensory neurons and fibers were not. Robust co-localization between GFP and neurofilament-200 (NF-200) as well as GFP and GAP-43 was observed at both the rostral and caudal bridge/tissue interface. No evidence of similar regeneration was observed in mice that received gelfoam at the lesion site as controls. Minimal co-localization between GFP reporter labeling and macrophage markers was observed. Taken together, these data suggest that axons originating from descending fiber tracts regenerated, entered into the PLG bridge at the rostral margin, continued through the bridge site, and exited to re-enter host tissue at the caudal edge of the intact bridge. Finally, regeneration through implanted bridges was associated with a reduction in ipsilateral forelimb errors on a horizontal ladder task.Published by Elsevier Ltd.

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BAC Transgenic Mice and the GENSAT Database of Engineered Mouse Strains

Cited by 63 publications

References 32 publications

Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2

Direct Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2

Agouti-related peptide plays a critical role in leptin's effects on female puberty and reproduction

Biomaterial bridges enable regeneration and re-entry of corticospinal tract axons into the caudal spinal cord after SCI: Association with recovery of forelimb function

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