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Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage.

ABSTRACT: Neural stem cells (NSCs) yield both neuronal and glial progeny, but their differentiation potential toward multiple region-specific neuron types remains remarkably poor. In contrast, embryonic stem cell (ESC) progeny readily yield region-specific neuronal fates in response to appropriate developmental signals. Here we demonstrate prospective and clonal isolation of neural rosette cells (termed R-NSCs), a novel NSC type with broad differentiation potential toward CNS and PNS fates and capable of in vivo engraftment. R-NSCs can be derived from human and mouse ESCs or from neural plate stage embryos. While R-NSCs express markers classically associated with NSC fate, we identified a set of genes that specifically mark the R-NSC state. Maintenance of R-NSCs is promoted by activation of SHH and Notch pathways. In the absence of these signals, R-NSCs rapidly lose rosette organization and progress to a more restricted NSC stage. We propose that R-NSCs represent the first characterized NSC stage capable of responding to patterning cues that direct differentiation toward region-specific neuronal fates. In addition, the R-NSC-specific genetic markers presented here offer new tools for harnessing the differentiation potential of human ESCs.

SUBMITTER: Elkabetz Y

PROVIDER: S-EPMC2192751 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage.

Elkabetz Yechiel Y Panagiotakos Georgia G Al Shamy George G Socci Nicholas D ND Tabar Viviane V Studer Lorenz L

Genes & development 20080101 2

Neural stem cells (NSCs) yield both neuronal and glial progeny, but their differentiation potential toward multiple region-specific neuron types remains remarkably poor. In contrast, embryonic stem cell (ESC) progeny readily yield region-specific neuronal fates in response to appropriate developmental signals. Here we demonstrate prospective and clonal isolation of neural rosette cells (termed R-NSCs), a novel NSC type with broad differentiation potential toward CNS and PNS fates and capable of ...[more]

PMID: 18198334

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Project description:The superficial layers of the medial entorhinal cortex (MEC) contain spatially selective neurons that are crucial for spatial navigation and memory. These highly specialized neurons include grid cells, border cells, head-direction cells, and irregular spatially selective cells. In addition, MEC neurons display a large variability in their spike patterns at a millisecond time scale. In this study, we analyzed spike trains of neurons in the MEC superficial layers of mice and found that these neurons can be classified into two groups based on their propensity to fire spike doublets at 125-250 Hz. The two groups, labeled "bursty" and "non-bursty" neurons, differed in their spike waveforms and interspike interval adaptation but displayed a similar mean firing rate. Grid cell spatial periodicity was more commonly observed in bursty than in non-bursty neurons. In contrast, most neurons with head-direction selectivity or those that fired at the border of the environment were non-bursty neurons. During theta oscillations, both bursty and non-bursty neurons fired preferentially near the end of the descending phase of the cycle, but the spikes of bursty neurons occurred at an earlier phase than those of non-bursty neurons. Finally, analysis of spike-time crosscorrelations between simultaneously recorded neurons suggested that the two cell classes are differentially coupled to fast-spiking interneurons: bursty neurons were twice as likely to have excitatory interactions with putative interneurons as non-bursty neurons. These results demonstrate that bursty and non-bursty neurons are differentially integrated in the MEC network and preferentially encode distinct spatial signals.Significance statementWe report that neurons in the superficial layers of the medial entorhinal cortex can be classified based on their tendency to fire bursts of action potentials at 125-250 Hz. The relevance of this classification is demonstrated by the types of spatial information preferentially encoded by bursty and non-bursty neurons. Grid-like spatial periodicity is more commonly observed in bursty neurons, whereas most cells with head-direction selectivity or those that are firing at the border of the environment are non-bursty neurons. This work indicates that the spatial firing patterns of neurons in the medial entorhinal cortex can be predicted by electrophysiological features reflecting the synaptic inputs and/or integrating properties of the neurons.

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Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage.

Publications

Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage.

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