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Cpg15 and cpg15-2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival.

ABSTRACT: Many ligands that affect nervous system development are members of gene families that function together to coordinate the assembly of complex neural circuits. cpg15/neuritin encodes an extracellular ligand that promotes neurite growth, neuronal survival, and synaptic maturation. Here we identify cpg15-2 as the only paralogue of cpg15 in the mouse and human genome. Both genes are expressed predominantly in the nervous system, where their expression is regulated by activity. cpg15-2 expression increases by more than twofold in response to kainate-induced seizures and nearly fourfold in the visual cortex in response to 24 hours of light exposure following dark adaptation. cpg15 and cpg15-2 diverge in their spatial and temporal expression profiles. cpg15-2 mRNA is most abundant in the retina and the olfactory bulb, as opposed to the cerebral cortex and the hippocampus for cpg15. In the retina, they differ in their cell-type specificity. cpg15 is expressed in retinal ganglion cells, whereas cpg15-2 is predominantly in bipolar cells. Developmentally, onset of cpg15-2 expression is delayed compared with cpg15 expression. CPG15-2 is glycosylphosphatidylinositol (GPI) anchored to the cell membrane and, like CPG15, can be released in a soluble-secreted form, but with lower efficiency. CPG15 and CPG15-2 were found to form homodimers and heterodimers with each other. In hippocampal explants and dissociated cultures, CPG15 and CPG15-2 promote neurite growth and neuronal survival with similar efficacy. Our findings suggest that CPG15 and CPG15-2 perform similar cellular functions but may play distinct roles in vivo through their cell-type- and tissue-specific transcriptional regulation.

SUBMITTER: Fujino T

PROVIDER: S-EPMC2828060 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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cpg15 and cpg15-2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival.

Fujino Tadahiro T Wu Zhen Z Lin Walter C WC Phillips Marnie A MA Nedivi Elly E

The Journal of comparative neurology 20080401 5

Many ligands that affect nervous system development are members of gene families that function together to coordinate the assembly of complex neural circuits. cpg15/neuritin encodes an extracellular ligand that promotes neurite growth, neuronal survival, and synaptic maturation. Here we identify cpg15-2 as the only paralogue of cpg15 in the mouse and human genome. Both genes are expressed predominantly in the nervous system, where their expression is regulated by activity. cpg15-2 expression inc ...[more]

PMID: 18265009

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Project description:The present study focuses on the function of cpg15, a neurotrophic factor, in ischemic neuronal recovery using transient global cerebral ischemic (TGI) mouse model and oxygen-glucose deprivation (OGD)-treated primary cultured cells. The results showed that expression of cpg15 proteins in astrocytes, predominantly the soluble form, was significantly increased in mouse hippocampus after TGI and in the cultured astrocytes after OGD. Addition of the medium from the cpg15-overexpressed astrocytic culture into the OGD-treated hippocampal neuronal cultures reduces the neuronal injury, whereas the recovery of neurite outgrowths of OGD-injured neurons was prevented when cpg15 in the OGD-treated astrocytes was knocked down, or the OGD-treated-astrocytic medium was immunoadsorbed by cpg15 antibody. Furthermore, lentivirus-delivered knockdown of cpg15 expression in mouse hippocampal astrocytes diminishes the dendritic branches and exacerbates injury of neurons in CA1 region after TGI. In addition, treatment with inhibitors of MEK1/2, PI3K, and TrkA decreases, whereas overexpression of p-CREB, but not dp-CREB, increases the expression of cpg15 in U118 or primary cultured astrocytes. Also, it is observed that the Flag-tagged soluble cpg15 from the astrocytes transfected with Flag-tagged cpg15-expressing plasmids adheres to the surface of neuronal bodies and the neurites. In conclusion, our results suggest that the soluble cpg15 from astrocytes induced by ischemia could ameliorate the recovery of the ischemic-injured hippocampal neurons via adhering to the surface of neurons. The upregulated expression of cpg15 in astrocytes may be activated via MAPK and PI3K signal pathways, and regulation of CREB phosphorylation.SIGNIFICANCE STATEMENT Neuronal plasticity plays a crucial role in the amelioration of neurological recovery of ischemic injured brain, which remains a challenge for clinic treatment of cerebral ischemia. cpg15 as a synaptic plasticity-related factor may participate in promoting the recovery process; however, the underlying mechanisms are still largely unknown. The objective of this study is to reveal the function and mechanism of neuronal-specific cpg15 expressed in astrocytes after ischemia induction, in promoting the recovery of injured neurons. Our findings provided new mechanistic insight into the neurological recovery, which might help develop novel therapeutic options for cerebral ischemia via astrocytic-targeting interference of gene expression.

Dataset Information

Cpg15 and cpg15-2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival.

Publications

cpg15 and cpg15-2 constitute a family of activity-regulated ligands expressed differentially in the nervous system to promote neurite growth and neuronal survival.

Similar Datasets

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