Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development. Shamis, Y; Cullen, DE; Liu, L; Yang, G; Ng, SF; Xiao, L; Bell, FT; Ray, C; Takikawa, S; Moskowitz, IP; Cai, CL; Yang, X; Li, X Proceedings of the National Academy of Sciences of the United States of America
112
E2020-9
2015
概要を表示する
Zfp57 is a maternal-zygotic effect gene that maintains genomic imprinting. Here we report that Zfp57 mutants exhibited a variety of cardiac defects including atrial septal defect (ASD), ventricular septal defect (VSD), thin myocardium, and reduced trabeculation. Zfp57 maternal-zygotic mutant embryos displayed more severe phenotypes with higher penetrance than the zygotic ones. Cardiac progenitor cells exhibited proliferation and differentiation defects in Zfp57 mutants. ZFP57 is a master regulator of genomic imprinting, so the DNA methylation imprint was lost in embryonic heart without ZFP57. Interestingly, the presence of imprinted DLK1, a target of ZFP57, correlated with NOTCH1 activation in cardiac cells. These results suggest that ZFP57 may modulate NOTCH signaling during cardiac development. Indeed, loss of ZFP57 caused loss of NOTCH1 activation in embryonic heart with more severe loss observed in the maternal-zygotic mutant. Maternal and zygotic functions of Zfp57 appear to play redundant roles in NOTCH1 activation and cardiomyocyte differentiation. This serves as an example of a maternal effect that can influence mammalian organ development. It also links genomic imprinting to NOTCH signaling and particular developmental functions. | | 25848000
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Hypocretin1/orexinA-immunoreactive axons form few synaptic contacts on rat ventral tegmental area neurons that project to the medial prefrontal cortex. Del Cid-Pellitero, E; Garzón, M BMC neuroscience
15
105
2014
概要を表示する
Hypocretins/orexins (Hcrt/Ox) are hypothalamic neuropeptides involved in sleep-wakefulness regulation. Deficiency in Hcrt/Ox neurotransmission results in the sleep disorder narcolepsy, which is characterized by an inability to maintain wakefulness. The Hcrt/Ox neurons are maximally active during wakefulness and project widely to the ventral tegmental area (VTA). A dopamine-containing nucleus projecting extensively to the cerebral cortex, the VTA enhances wakefulness. In the present study, we used retrograde tracing from the medial prefrontal cortex (mPFC) to examine whether Hcrt1/OxA neurons target VTA neurons that could sustain behavioral wakefulness through their projections to mPFC.The retrograde tracer Fluorogold (FG) was injected into mPFC and, after an optimal survival period, sections through the VTA were processed for dual immunolabeling of anti-FG and either anti-Hcrt1/OxA or anti-TH antisera. Most VTA neurons projecting to the mPFC were located in the parabrachial nucleus of the ipsilateral VTA and were non-dopaminergic. Only axonal profiles showed Hcrt1/OxA-immunoreactivity in VTA. Hcrt1/OxA reactivity was observed in axonal boutons and many unmyelinated axons. The Hcrt1/OxA immunoreactivity was found filling axons but it was also observed in parts of the cytoplasm and dense-core vesicles. Hcrt1/OxA-labeled boutons frequently apposed FG-immunolabeled dendrites. However, Hcrt1/OxA-labeled boutons rarely established synapses, which, when they were established, were mainly asymmetric (excitatory-type), with either FG-labeled or unlabeled dendrites.Our results provide ultrastructural evidence that Hcrt1/OxA neurons may exert a direct synaptic influence on mesocortical neurons that would facilitate arousal and wakefulness. The paucity of synapses, however, suggest that the activity of VTA neurons with cortical projections might also be modulated by Hcrt1/OxA non-synaptic actions. In addition, Hcrt1/OxA could modulate the postsynaptic excitatory responses of VTA neurons with cortical projections to a co-released excitatory transmitter from Hcrt1/OxA axons. Our observation of Hcrt1/OxA targeting of mesocortical neurons supports Hcrt1/OxA wakefulness enhancement in the VTA and could help explain the characteristic hypersomnia present in narcoleptic patients. | | 25194917
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Long-term exercise is a potent trigger for ΔFosB induction in the hippocampus along the dorso-ventral axis. Nishijima, T; Kawakami, M; Kita, I PloS one
8
e81245
2013
概要を表示する
Physical exercise improves multiple aspects of hippocampal function. In line with the notion that neuronal activity is key to promoting neuronal functions, previous literature has consistently demonstrated that acute bouts of exercise evoke neuronal activation in the hippocampus. Repeated activating stimuli lead to an accumulation of the transcription factor ΔFosB, which mediates long-term neural plasticity. In this study, we tested the hypothesis that long-term voluntary wheel running induces ΔFosB expression in the hippocampus, and examined any potential region-specific effects within the hippocampal subfields along the dorso-ventral axis. Male C57BL/6 mice were housed with or without a running wheel for 4 weeks. Long-term wheel running significantly increased FosB/ΔFosB immunoreactivity in all hippocampal regions measured (i.e., in the DG, CA1, and CA3 subfields of both the dorsal and ventral hippocampus). Results confirmed that wheel running induced region-specific expression of FosB/ΔFosB immunoreactivity in the cortex, suggesting that the uniform increase in FosB/ΔFosB within the hippocampus is not a non-specific consequence of running. Western blot data indicated that the increased hippocampal FosB/ΔFosB immunoreactivity was primarily due to increased ΔFosB. These results suggest that long-term physical exercise is a potent trigger for ΔFosB induction throughout the entire hippocampus, which would explain why exercise can improve both dorsal and ventral hippocampus-dependent functions. Interestingly, we found that FosB/ΔFosB expression in the DG was positively correlated with the number of doublecortin-immunoreactive (i.e., immature) neurons. Although the mechanisms by which ΔFosB mediates exercise-induced neurogenesis are still uncertain, these data imply that exercise-induced neurogenesis is at least activity dependent. Taken together, our current results suggest that ΔFosB is a new molecular target involved in regulating exercise-induced hippocampal plasticity. | | 24282574
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Wild-type neural progenitors divide and differentiate normally in an amyloid-rich environment. Yetman, MJ; Jankowsky, JL The Journal of neuroscience : the official journal of the Society for Neuroscience
33
17335-41
2013
概要を表示する
Adult neurogenesis is modulated by a balance of extrinsic signals and intrinsic responses that maintain production of new granule cells in the hippocampus. Disorders that disrupt the proliferative niche can impair this process, and alterations in adult neurogenesis have been described in human autopsy tissue and transgenic mouse models of Alzheimer's disease. Because exogenous application of aggregated Aβ peptide is neurotoxic in vitro and extracellular Aβ deposits are the main pathological feature recapitulated by mouse models, cell-extrinsic effects of Aβ accumulation were thought to underlie the breakdown of hippocampal neurogenesis observed in Alzheimer's models. We tested this hypothesis using a bigenic mouse in which transgenic expression of APP was restricted to mature projection neurons. These mice allowed us to examine how wild-type neural progenitor cells responded to high levels of Aβ released from neighboring granule neurons. We find that the proliferation, determination, and survival of hippocampal adult-born granule neurons are unaffected in the APP bigenic mice, despite abundant amyloid pathology and robust neuroinflammation. Our findings suggest that Aβ accumulation is insufficient to impair adult hippocampal neurogenesis, and that factors other than amyloid pathology may account for the neurogenic deficits observed in transgenic models with more widespread APP expression. | | 24174666
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Expression of hepatocyte epidermal growth factor receptor, FAS and glypican 3 in EpCAM-positive regenerative clusters of hepatocytes, cholangiocytes, and progenitor cells in human liver failure. Hattoum, A; Rubin, E; Orr, A; Michalopoulos, GK Human pathology
44
743-9
2013
概要を表示する
Liver regeneration under normal circumstances proceeds through proliferation of all cellular elements of the liver. Studies with rodent models have shown that when proliferation of hepatocytes is inhibited, progenitor cells arising from the biliary compartment transdifferentiate into "oval/progenitor" cells, which proceed to differentiate into hepatocytes. Recent studies have shown that the same pathways may operate in human liver failure. The growth factor receptors (HGF [hepatocyte growth factor] receptor) and epidermal growth factor receptor are key mitogenic receptors for both hepatocytes and progenitor cells. Our current study used the biliary and progenitor marker EpCAM (epithelial cell adhesion molecule) to detect "regenerative clusters" of mixed cholangiocyte-hepatocyte differentiation. We determined that expression of metabolic equivalent and epidermal growth factor receptor occurs in biliary cells, progenitor cells, and hepatocytes, whereas activation of metabolic equivalent and epidermal growth factor receptor is limited to regenerative cluster hepatocytes. These histologic events are associated with expression of apoptosis-inducing FAS and mitoinhibitory protein glypican 3. Cell proliferation was overall suppressed in regenerative clusters. Transdifferentiation of biliary and progenitor cells appears to be regulated by a complex interaction of signals promoting and arresting growth. | | 23114924
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Medial prefrontal cortex receives input from dorsal raphe nucleus neurons targeted by hypocretin1/orexinA-containing axons. E Del Cid-Pellitero,M Garzón Neuroscience
172
2011
概要を表示する
The medial prefrontal cortex (mPFC) is strongly involved in cognition and behavior. It receives input from brainstem nuclei implicated in behavioral wakefulness and electrographic cortical activation, such as the dorsal raphe nucleus (DRN). Moreover, the hypocretinergic/orexinergic (Hcrt/Ox) hypothalamic neurons innervate DRN, thus modulating its activity and presumably allowing transitions between sleep-wakefulness cycle states. Dysfunction in this system is associated with narcolepsy. In this study we aimed to determine the precise location of DRN neurons projecting to mPFC and the extent to which they contain serotonin (5-hydroxytryptamine); we have also assessed whether Hcrt1/OxA neurons innervate DRN neurons that could sustain behavioral wakefulness through their projections to mPFC. The retrograde tracer Fluorogold was injected into mPFC and DRN sections were processed for double immunolabeling of anti-Fluorogold and either anti-5-hydroxytryptamine or anti-Hcrt1/OxA antisera. Most DRN neurons projecting to mPFC were located in the ventral sector of the rostral and intermediate DRN, and around half of them were serotonergic. Hcrt1/OxA-immunoreactivity in DRN was observed in unmyelinated axons and axon boutons (varicosities or axon terminals). Hcrt1/OxA immunoreactivity was observed within the cytoplasm and in dense-cored vesicles of these axons. Hcrt1/OxA-labeled boutons established both asymmetric synapses (n=30) and appositional contacts (n=102) with Fluorogold-labeled dendrites belonging to DRN neurons projecting to mPFC. Our results show that Hcrt1/OxA neurons may exert a direct synaptic influence on DRN neurons that could facilitate wakefulness, although other non-synaptic actions through volume transmission are also suggested. | | 21036204
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Scaffolds containing growth factors and extracellular matrix induce hepatocyte proliferation and cell migration in normal and regenerating rat liver. Hammond JS, Gilbert TW, Howard D, Zaitoun A, Michalopoulos G, Shakesheff KM, Beckingham IJ, Badylak SF. Journal of hepatology
54
279-87
2011
概要を表示する
Intrahepatic drug delivery from implantable scaffolds is being developed as a strategy to modulate growth and enhance regeneration at the time of liver resection. In this study we examine the effects of scaffolds containing hepatocyte growth factor, epidermal growth factor, fibroblast growth factor 1, fibroblast growth factor 2, and liver-derived extracellular matrix (L-ECM) when implanted into normal and partially hepatectomized rat livers. | | 21126791
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Hypocretin1/OrexinA axon targeting of laterodorsal tegmental nucleus neurons projecting to the rat medial prefrontal cortex. Cid-Pellitero, Ed; Garzón, M Cerebral cortex (New York, N.Y. : 1991)
21
2762-73
2011
概要を表示する
Cortical activation and goal-directed behaviors characterize wakefulness. One cortical region especially involved in these phenomena is the medial prefrontal cortex (mPFC), which receives many inputs from cholinergic-containing neurons in brain stem structures implicated in arousal and wakefulness, such as the laterodorsal tegmental nucleus (LDT). Hypocretins/orexins (Hcrt/Ox), whose dysfunction is linked to narcolepsy, maintains arousal and stabilizes sleep-wakefulness states. We aim to determine if Hcrt1/OxA axons (1) innervate LDT neurons projecting to the mPFC, a target that would allow them to sustain arousal and wakefulness, and (2) target preferentially cholinergic versus noncholinergic LDT neurons. The retrograde tracer Fluorogold (FG) was injected in the rat mPFC, and dual immunolabeling of anti-FG and either anti-choline acetyltransferase (ChAT) or anti-Hcrt1/OxA antisera was determined in LDT. Also, actual Hcrt1/OxA targeting of cholinergic LDT neurons was ascertained by dual anti-Hcrt1/OxA and anti-ChAT detection in additional noninjected animals. Many LDT FG-labeled neurons were cholinergic (52.05 ± 3.72%). Hcrt1/OxA immunoprecipitate was observed in cytoplasm and granular vesicles within axons. Some Hcrt1/OxA-containing axons established asymmetric excitatory-type synapses with either unlabeled (46/438) or FG-labeled (7/438) dendrites. One-third of the target neurons were ChAT labeled. Hcrt1/OxA excitatory input to LDT neurons projecting to mPFC probably contributes to the wakefulness-enhancing actions of Hcrt/Ox impaired in narcoleptics. | Immunohistochemistry | 21508301
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Hypocretin1OrexinA-containing axons innervate locus coeruleus neurons that project to the rat medial prefrontal cortex. Implication in the sleep-wakefulness cycle and cortical activation. Cid-Pellitero ED, Garzón M Synapse
2011
概要を表示する
The Hypocretin1/OrexinA (Hcrt1/OxA) neuropeptides are found in a group of posterolateral hypothalamus neurons and are involved in sleep-wakefulness cycle regulation. Hcrt1/OxA neurons project widely to brainstem aminergic structures, such as the locus coeruleus (LC), which are involved in maintenance of wakefulness and EEG activation through intense projections to the medial prefrontal cortex (mPFC). Moreover, defects of the Hcrt1/OxA system are linked to narcolepsy, a disorder characterized by excessive diurnal hypersomnia and REM state disturbance. We aimed to determine whether Hcrt1/OxA neurons innervate LC neurons (noradrenergic and nonnoradrenergic) that project to the mPFC, thereby sustaining behavioral wakefulness. To assess this, we used retrograde tracing from mPFC injections and either Hcrt1/OxA or tyrosine hydroxylase (TH) immunohistochemical labeling in single sections of rat LC. The retrograde tracer Fluorogold (FG) was microinjected into mPFC and, at optimal survival periods, sections through the LC were processed for dual immunolabeling of anti-FG and either anti-Hcrt1/OxA or anti-TH antisera. Many LC neurons projecting to mPFC were nonnoradrenergic. Electron microscopy revealed a prominent localization of Hcrt1/OxA in unmyelinated axons and axon boutons (varicosities and axon terminals) within the LC. Hcrt1/OxA-immunoreactive axon boutons frequently apposed (104/1907) or made asymmetric excitatory-type synapses (60/1907) with FG-immunolabeled dendrites, indicating that Hcrt1/OxA can modulate the activity of LC neurons with cortical projections. Our results show that Hcrt1/OxA hypothalamic neurons likely excite LC neurons that project to the mPFC, and thus activate EEG and facilitate wakefulness. In narcoleptics, who are deficient in Hcrt1/OxA, impairment of this Hcrt1/OxA hypothalamic input to LC might contribute to the appearance of excessive daytime sleepiness. Synapse , 2011. © 2011 Wiley-Liss, Inc.Copyright © 2011 Wiley-Liss, Inc. | | 21308795
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Coexpression of VGLUT1 and VGLUT2 in trigeminothalamic projection neurons in the principal sensory trigeminal nucleus of the rat. Shun-Nan Ge,Yun-Fei Ma,Hiroyuki Hioki,Yan-Yan Wei,Takeshi Kaneko,Noboru Mizuno,Guo-Dong Gao,Jin-Lian Li The Journal of comparative neurology
518
2010
概要を表示する
VGLUT1 and VGLUT2 have been reported to show complementary distributions in most brain regions and have been assumed to define distinct functional elements. In the present study, we first investigated the expression of VGLUT1 and VGLUT2 in the trigeminal sensory nuclear complex of the rat by dual-fluorescence in situ hybridization. Although VGLUT1 and/or VGLUT2 mRNA signals were detected in all the nuclei, colocalization was found only in the principal sensory trigeminal nucleus (Vp). About 64% of glutamatergic Vp neurons coexpressed VGLUT1 and VGLUT2, and the others expressed either VGLUT1 or VGLUT2, indicating that Vp neurons might be divided into three groups. We then injected retrograde tracer into the thalamic regions, including the posteromedial ventral nucleus (VPM) and posterior nuclei (Po), and observed that the majority of both VGLUT1- and VGLUT2-expressing Vp neurons were retrogradely labeled with the tracer. We further performed anterograde labeling of Vp neurons and observed immunoreactivies for anterograde tracer, VGLUT1, and VGLUT2 in the VPM and Po. Most anterogradely labeled axon terminals showed immunoreactivities for both VGLUT1 and VGLUT2 in the VPM and made asymmetric synapses with dendritic profiles of VPM neurons. On the other hand, in the Po, only a few axon terminals were labeled with anterograde tracer, and they were positive only for VGLUT2. The results indicated that Vp neurons expressing VGLUT1 and VGLUT2 project to the VPM, but not to the Po, although the functional differences of three distinct populations of Vp neurons, VGLUT1-, VGLUT2-, and VGLUT1/VGLUT2-expressing ones, remain unsettled. | | 20533365
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