Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance

Astrocytes may function as mediators of the impact of noradrenaline on neuronal function. Activation of glial α1-adrenergic receptors triggers rapid astrocytic Ca2+ elevation and facilitates synaptic plasticity, while activation of β-adrenergic receptors elevates cAMP levels and modulates memory consolidation. However, the dynamics of these processes in behaving mice remain unexplored, as do the interactions between the distinct second messenger pathways. Here we simultaneously monitored astrocytic Ca2+ and cAMP and demonstrate that astrocytic second messengers are regulated in a temporally distinct manner. In behaving mice, we found that while an abrupt facial air puff triggered transient increases in noradrenaline release and large cytosolic astrocytic Ca2+ elevations, cAMP changes were not detectable. By contrast, repeated aversive stimuli that lead to prolonged periods of vigilance were accompanied by robust noradrenergic axonal activity and gradual sustained cAMP increases. Our findings suggest distinct astrocytic signaling pathways can integrate noradrenergic activity during vigilance states to mediate distinct functions supporting memory

A Large-Scale Zebrafish Gene Knockout Resource for the Genome-Wide Study of Gene Function

With the completion of the zebrafish genome sequencing project, it becomes possible to analyze the function of zebrafish genes in a systematic way. The first step in such an analysis is to inactivate each protein-coding gene by targeted or random mutation. Here we describe a streamlined pipeline using proviral insertions coupled with high-throughput sequencing and mapping technologies to widely mutagenize genes in the zebrafish genome. We also report the first 6144 mutagenized and archived F1’s predicted to carry up to 3776 mutations in annotated genes. Using in vitro fertilization, we have rescued and characterized ~0.5% of the predicted mutations, showing mutation efficacy and a variety of phenotypes relevant to both developmental processes and human genetic diseases. Mutagenized fish lines are being made freely available to the public through the Zebrafish International Resource Center. These fish lines establish an important milestone for zebrafish genetics research and should greatly facilitate systematic functional studies of the vertebrate genome

〈Originals〉Trib1 and Trib2 inhibit granulocytic differentiation by suppressing Akt pathway

[Abstract] Background :Overexpression of Tribbles homolog 1 (Tribl) and Tribbles homolog 2 (Trib2) in hematopoietic stem/progenitor cells evokes acute myeloid leukemia (AML) in murine transplantation models. Degradation of CCAAT-enhancer-binding-protein α (C/EBPα) plays a crucial role in Trib1 or Trib2-induced AML. However, because C/EBPα knockout mice do not develop AML, it is likely that Trib1 and Trib2 influence other signaling pathways besides C/EBPα. Elevated Akt phosphorylation is considered to contribute to the development of AML. In contrast, two groups recently reported that reduced Akt activity is involved in the pathogenesis of leukemia. We performed this study to reveal the role of Akt signaling in Trib family-induced AML.Methods : G-CSF-induced granulocytic differentiation of 32D cells was assessed morphologically and phenotypically. G-CSF-induced signaling wasassessed by Westernblotting. Results : Overexpression of Trib1 or Trib2 inhibited GCSF-induced granulocytic differentiation of 32D cells, which was accompanied by reduced Akt phosphorylation. Also, an Akt inhibitor API-2 blocked G-CSF-induced granulocytic differentiation independently of C/EBPα degradation.　Furthermore, retroviral C/EBPα restoration did not completely abolish the differentiation block caused by Trib1 and Trib2. Conclusion :Trib1 and Trib2 block granulocytic differentiation, at least partially, by suppressing Akt phosphorylation

Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance

Astrocytes may function as mediators of the impact of noradrenaline on neuronal function. Activation of glial α1-adrenergic receptors triggers rapid astrocytic Ca2+ elevation and facilitates synaptic plasticity, while activation of β-adrenergic receptors elevates cAMP levels and modulates memory consolidation. However, the dynamics of these processes in behaving mice remain unexplored, as do the interactions between the distinct second messenger pathways. Here we simultaneously monitored astrocytic Ca2+ and cAMP and demonstrate that astrocytic second messengers are regulated in a temporally distinct manner. In behaving mice, we found that while an abrupt facial air puff triggered transient increases in noradrenaline release and large cytosolic astrocytic Ca2+ elevations, cAMP changes were not detectable. By contrast, repeated aversive stimuli that lead to prolonged periods of vigilance were accompanied by robust noradrenergic axonal activity and gradual sustained cAMP increases. Our findings suggest distinct astrocytic signaling pathways can integrate noradrenergic activity during vigilance states to mediate distinct functions supporting memory

Author Correction: Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Author Correction: Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance

An amendment to this paper has been published and can be accessed via a link at the top of the paper